Organic compounds

ABSTRACT

The invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT 2A  receptor, the serotonin transporter (SERT), pathways involving the dopamine D 1  and D 2  receptor signaling system, and/or the μ-opioid receptor.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/660,615, filed Jul. 26, 2017, which is a Continuation-in-Part under35 U.S.C. § 111 of International Application PCT/US2017/015178, filedJan. 26, 2017, designating the United States and claiming the benefit ofU.S. Provisional Application No. 62/440,130, filed Dec. 29, 2016, andU.S. Provisional Application No. 62/287,264, filed Jan. 26, 2016, thecontents of each of which are incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The invention relates to particular substituted heterocycle fusedgamma-carbolines, their prodrugs, in free, solid, pharmaceuticallyacceptable salt and/or substantially pure form as described herein,pharmaceutical compositions thereof, and methods of use in the treatmentof diseases involving the 5-HT_(2A) receptor, the serotonin transporter(SERT), pathways involving dopamine D₁ and D₂ receptor signalingsystems, and/or the μ-opioid receptor, e.g., diseases or disorders suchas anxiety, psychosis, schizophrenia, sleep disorders, sexual disorders,migraine, conditions associated with cephalic pain, social phobias,gastrointestinal disorders such as dysfunction of the gastrointestinaltract motility and obesity; depression and mood disorders associatedwith psychosis or Parkinson's disease; psychosis such as schizophreniaassociated with depression; bipolar disorder; mood disorders; drugdependencies, such as opiate dependency and alcohol dependency, drugwithdrawal symptoms, and other psychiatric and neurological conditions,as well as to combinations with other agents. In addition, suchcompounds and compositions are useful in methods of treatment ofobsessive-compulsive disorder (OCD), obsessive-compulsive personalitydisorder (OCPD), and related disorders. In some embodiments, the diseaseor disorders may include treatment-resistant depression, cocainedependency, and/or amphetamine dependency.

BACKGROUND OF THE INVENTION

Substituted heterocycle fused gamma-carbolines are known to be agonistsor antagonists of 5-HT₂ receptors, particularly 5-HT_(2A) and 5-HT_(2C)receptors, in treating central nervous system disorders. These compoundshave been disclosed in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680, and U.S. RE39679, as novel compoundsuseful for the treatment of disorders associated with 5-HT_(2A) receptormodulation such as obesity, anxiety, depression, psychosis,schizophrenia, sleep disorders, sexual disorders migraine, conditionsassociated with cephalic pain, social phobias, gastrointestinaldisorders such as dysfunction of the gastrointestinal tract motility,and obesity. PCT/US08/03340 (WO 2008/112280) and U.S. application Ser.No. 10/786,935 also disclose methods of making substituted heterocyclefused gamma-carbolines and uses of these gamma-carbolines as serotoninagonists and antagonists useful for the control and prevention ofcentral nervous system disorders such as addictive behavior and sleepdisorders.

In addition, WO/2009/145900 discloses use of particular substitutedheterocycle fused gamma-carbolines for the treatment of a combination ofpsychosis and depressive disorders as well as sleep, depressive and/ormood disorders in patients with psychosis or Parkinson's disease. Inaddition to disorders associated with psychosis and/or depression, thispatent application discloses and claims use of these compounds at a lowdose to selectively antagonize 5-HT_(2A) receptors without affecting orminimally affecting dopamine D₂ receptors, thereby useful for thetreatment of sleep disorders without the side effects associated withhigh occupancy of the dopamine D₂ pathways or side effects of otherpathways (e.g., GABA_(A) receptors) associated with conventionsedative-hypnotic agents (e.g., benzodiazepines) including but notlimited to the development of drug dependency, muscle hypotonia,weakness, headache, blurred vision, vertigo, nausea, vomiting,epigastric distress, diarrhea, joint pains, and chest pains. WO2009/114181 also discloses of methods of preparing toluenesulfonic acidaddition salt crystals of these substituted heterocycle fusedgamma-carbolines.

Obsessive-compulsive disorder (OCD) and related disorders, have becomehighly prevalent and are difficult to treat. OCD is estimated to affectabout 2.3% of people at some point in their lives, and during a givenyear, it is estimated than 1.2% of people worldwide suffer from thedisorder. Half of people who suffer from OCD begin to show symptomsbefore the age of 20, which can seriously affect their ability to obtainan adequate and effective education. Without effective treatment,however, the disease can last for decades. The mainstay of pharmacologicOCD treatment is with selective serotonin reuptake inhibitors (SSRIs). Asecond line of therapy is with antipsychotic agents, such asclomipramine, risperidone, quetiapine and olanzapine. A significantnumber of patients either do not respond to these agents, or cannothandle the side effects caused by these agents. More recently, it hasbeen reported that the opioid analgesic tramadol may be effective intreating OCD. Opiates operate by an entirely different pathway fromtraditional OCD treatment agents, so they offer the possibility oftreatment for people who cannot take the traditional serotonergic agentsor for whom these agents are ineffective. However, strong opiate agentscan be addictive, and their use may be contraindicated in some patients.There thus remains an urgent need for new treatments for OCD and relateddisorders.

SUMMARY OF THE INVENTION

The present disclosure provides Compounds of Formula I that are usefulfor the treatment or prophylaxis of central nervous system disorders. Ina first aspect, the present disclosure relates to a compound (CompoundI) of Formula I:

-   -   wherein:    -   X is —NH— or —N(CH₃)—;    -   L is selected from O, NH, NR^(a), and S;    -   Z is —CH(O—R₁)—, —O— or —C(═O)—;    -   R¹ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅        alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a        straight chain, optionally saturated or unsaturated and        optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy        (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆        alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,        —C(O)—C₁₃ alkyl or —C(O)—Cis alkyl;    -   R^(a) is:        -   halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, or C₃₋₆            cycloalkyl, each of which can be independently substituted            with up to three independently selected R^(b) groups, for            example C-₁₋₃ haloalkyl or C₁₋₃ hydroxyalkyl; or        -   aryl optionally substituted with up to five independently            selected R^(b); and each R^(b) is independently selected            from H, halogen, NH₂, NO₂, OH, C(O)OH, CN, SO₃, and C₁₋₄            alkyl;    -   in free or salt form, for example in an isolated or purified        free or salt form.

The present disclosure provides additional exemplary embodiments of theCompound of Formula I, in free or salt form, for example in an isolatedor purified free or salt form, including:

-   -   1.1 Compound I, wherein L is —O—;    -   1.2 Compound I or 1.1, wherein Z is —CH(O—R₁)—;    -   1.3 Compound I or 1.1, wherein Z is —C(═O)—;    -   1.4 Compound I, wherein L is NH.    -   1.5 Compound I, wherein L is NR^(a);    -   1.6 Compound I, wherein L is S;    -   1.7 Compound I or any of 1.1-1.6, in solid form, for example in        solid salt form;    -   1.8 Compound I or any of 1.1-1.7, wherein Z is —CH(O—R₁)—;    -   1.9 Compound I, or any of 1.1-1.7, wherein Z is —C(═O)—;    -   1.10 Compound I, or any of 1.1-1.7, wherein Z is —O—;    -   1.11 Compound I or any of 1.1-1.10, wherein X is —NH—;    -   1.12 Compound I or any of 1.1-1.10, wherein X is —N(CH₃)—;    -   1.13 Compound I or any of 1.1-1.12, wherein L is —O— and X is        —N(CH₃)—;    -   1.14 Compound I or any of 1.1-1.12, wherein L is —O— and X is        —NH—;    -   1.15 Compound 1.13, wherein Z is —C(═O)—;    -   1.16 Compound 1.14, wherein Z is —C(═O)—;    -   1.17 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and        R₁ is H;    -   1.18 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and        R₁ is —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅ alkyl or —C(O)—C₁₆₋₂₁ alkyl;    -   1.19 Compound I or any of 1.1-1.14, wherein Z is —CH(O—R₁)— and        R₁ is selected from the group consisting of C(O)—C₃ alkyl,        —C(O)C₆ alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,        —C(O)—C₁₃ alkyl or —C(O)—Cis alkyl; for example, wherein R¹ is        acetyl, ethylcarbonyl, or propylcarbonyl;    -   1.20 Compound I or any of 1.1-1.12 or 1.17-1.19, wherein L is        NR^(a), and wherein R^(a) is: halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,        C₂₋₄ alkynyl, or C₃₋₆ cycloalkyl, each of which can be        independently substituted with up to three independently        selected R^(b) groups; or wherein R^(a) is aryl optionally        substituted with up to five independently selected R^(b);        wherein R^(b) is independently selected from H, halogen, NH₂,        NO₂, OH, C(O)OH, CN, SO₃, and C₁₋₄ alkyl;    -   1.21 Compound 1.20, wherein R^(a) is C₁₋₄ alkyl or C₃₋₆        cycloalkyl, optionally substituted with up to three        independently selected R^(b) groups;    -   1.22 Compound 1.20, wherein R^(a) is aryl, optionally        substituted with up to three independently selected R^(b)        groups;    -   1.23 Compound 1.20, wherein R^(a) is selected from the group        consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl,        sec-butyl, or phenyl;    -   1.24 Compound I, or any of 1.1-1.14 or 1.17-1.23, wherein Z is        —CH(O—R₁)—; and said carbon atom CH in the group —CH(O—R₁)— has        either the R configuration or the S configuration, or a mixture        thereof;    -   1.25 Compound 1.24, wherein the carbon atom CH is substantially        present in either the R configuration or the S configuration,        e.g., wherein the diastereomer having the R configuration or the        S configuration at this carbon is present in greater than 70%        diastereomeric excess, for example, greater than 75%, or greater        than 80%, or greater than 85%, or greater than 90%, or greater        than 95%, or greater than 97%, or greater than 98% or greater        than 99%, diastereomeric excess.    -   1.26 Compound I, or any of 1.1-1.25, wherein the compound is        selected from the group consisting of:

-   -   1.27 Compound I, or any of 1.1-1.25, wherein the compound is        selected from the group consisting of:

-   -   1.28 Compound I, or any of 1.1-1.28, in free form;    -   1.29 Compound I, or any of 1.1-1.28 in salt form, e.g.,        pharmaceutically acceptable salt form;    -   1.30 Compound I or any of 1.1-1.29 in solid form.    -   in free or salt form, for example in an isolated or purified        free or salt form.

In a second aspect, the present disclosure relates to a compound(Compound II) of Formula II:

-   -   wherein:        -   X is —NH— or —N(CH₃)—;        -   Y is —CH(O—R₁)— or —C(═O)—;        -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl,            —C(O)—C₆₋₁₅ alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said            alkyl is a straight chain, optionally saturated or            unsaturated and optionally substituted with one or more            hydroxy or C₁₋₂₂ alkoxy (e.g., ethoxy) groups, for example            R₁ is C(O)—C₃ alkyl, —C(O)C₆ alkyl, —C(O)—C₇ alkyl, —C(O)—C₉            alkyl, —C(O)—C₁₁ alkyl, —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl;    -   in free or salt form, for example in an isolated or purified        free or salt form.

The present disclosure provides additional exemplary embodiments of theCompound of Formula II, in free or salt form, for example in an isolatedor purified free or salt form, including:

-   -   2.1 Compound II, wherein X is —NH—;    -   2.2 Compound II, wherein X is —N(CH₃)—;    -   2.3 Compound II, or 2.1-2.4, wherein Y is —C(═O)—;    -   2.4 Compound II, wherein Y is —CH(O—R₁)—; i.e., having the        Formula II-A:

-   -   2.5 Compound II, or 2.1-2.4, wherein Y is —CH(O—R₁)—;    -   2.6 Compound II, wherein X is NH and Y is —C(═O)—; i.e., having        the Formula II-B:

-   -   2.7 Compound II, wherein X is —NH— and Y is —CH(O—R₁)—;    -   2.8 Compound II, wherein X is —NH— and Y is —CH(O—R₁)—, wherein        R₁ is H; i.e., having the Formula II-C:

-   -   2.9 Compound II, wherein X is —N(CH₃)— and Y is —C(═O)—; i.e.,        having the Formula II-D:

-   -   2.10 Compound II, wherein X is —N(CH₃)— and Y is —CH(O—R₁)—;    -   2.11 Compound II, wherein X is —N(CH₃)— and Y is —CH(O—R₁)—,        wherein R₁ is H; i.e., having the Formula II-E:

-   -   2.12 Compound II or any of 2.1-2.11, in solid form, for example        in solid salt form.

In a third aspect, the present disclosure relates to a compound(Compound III) of Formula III:

wherein:

-   -   X is —NH— or —N(CH₃)—;    -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅        alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a        straight chain, optionally saturated or unsaturated and        optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy        (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆        alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,        —C(O)—C₁₃ alkyl or —C(O)—C₁₅;

in free or salt form, for example in an isolated or purified free orsalt form.

The present disclosure provides additional exemplary embodiments of theCompound of Formula III, in free or salt form, for example in anisolated or purified free or salt form. including:

-   -   3.1 Compound III, wherein R₁ is H; i.e., having the Formula        III-A:

-   -    in free or salt form, for example in an isolated or purified        free or salt form;    -   3.2 Compound III or 3.1, wherein X is —NH—;    -   3.3 Compound III or 3.1, wherein X is —N(CH₃)—;    -   3.4 Compound 3.1, wherein X is —NH—; i.e., having the Formula        III-B:

-   -   3.5 Compound 3.1, wherein X is —N(CH₃)—; i.e., having the        Formula III-C:

-   -   3.6 Compound III or any of 3.1-3.5, wherein the Compound has a        diastereomeric excess of greater than 70%;    -   3.7 Compound III or any of 3.1-3.6, wherein the Compound has a        diastereomeric excess of greater than 80%;    -   3.8 Compound III or any of 3.1-3.7, wherein the Compound has a        diastereomeric excess of greater than 90%;    -   3.9 Compound III or any of 3.1-3.8, wherein the Compound has a        diastereomeric excess of greater than 95%;    -   3.10 Compound III or any of 3.1-3.9, wherein the Compound is in        substantially pure diastereomeric form (i.e., substantially free        from other diastereomers)    -   3.11 Compound III or any of 3.1-3.10, in solid form, for example        in solid salt form.

In a fourth aspect, the present disclosure relates to a compound(Compound IV) of Formula IV:

wherein:

-   -   X is —NH— or —N(CH₃)—;    -   R₁ is H, —C(O)—C₁₋₂₁ alkyl (e.g., —C(O)—C₁₋₅ alkyl, —C(O)—C₆₋₁₅        alkyl or —C(O)—C₁₆₋₂₁ alkyl), preferably said alkyl is a        straight chain, optionally saturated or unsaturated and        optionally substituted with one or more hydroxy or C₁₋₂₂ alkoxy        (e.g., ethoxy) groups, for example R₁ is C(O)—C₃ alkyl, —C(O)C₆        alkyl, —C(O)—C₇ alkyl, —C(O)—C₉ alkyl, —C(O)—C₁₁ alkyl,        —C(O)—C₁₃ alkyl or —C(O)—C₁₅ alkyl;

in free or salt form, for example in an isolated or purified free orsalt form.

The present disclosure provides additional exemplary embodiments of theCompound of Formula IV, in free or salt form, for example in an isolatedor purified free or salt form, including:

-   -   4.1 Compound IV, wherein R₁ is H; i.e., having the Formula IV-A:

-   -    in free or salt form, for example in an isolated or purified        free or salt form.    -   4.2 Compound IV or 4.1, wherein X is —NH—;    -   4.3 Compound IV or 4.1, wherein X is —N(CH₃)—;    -   4.4 Compound 4.1, wherein X is —NH—; i.e., having the Formula        IV-B:

-   -   4.5 Compound 4.1, wherein X is —N(CH₃)—; i.e., having the        Formula IV-C:

-   -   4.6 Compound IV or any of 4.1-4.5, wherein the Compound has a        diastereomeric excess of greater than 70%    -   4.7 Compound IV or any of 4.1-4.6, wherein the Compound has a        diastereomeric excess of greater than 80%    -   4.8 Compound IV or any of 4.1-4.7, wherein the Compound has a        diastereomeric excess of greater than 90%    -   4.9 Compound IV or any of 4.1-4.8, wherein the Compound has a        diastereomeric excess of greater than 95%    -   4.10 Compound IV or any of 4.1-4.9, wherein the Compound is in        substantially pure diastereomeric form (i.e., substantially free        from other diastereomers);    -   4.11 Compound IV or any of 4.1-4.10, in solid form, for example        in solid salt form.

In a fifth aspect, the present disclosure provides each of the foregoingCompound I or 1.1-1.30, Compound II or 2.1-2.12, Compound III or3.1-3.11, or Compound IV or 4.1-4.11 (hereinafter collectively“Compounds of Formulas I-IV et seq.” or “compounds of the disclosure”)in free or pharmaceutically acceptable salt form. The present disclosureprovides additional exemplary embodiments of the Compounds of FormulasI-IV et seq., including:

-   -   5.1 Compounds of Formulas I-IV et seq., wherein the salt is an        acid addition salt selected from hydrochloric, hydrobromic,        sulfuric, sulfamic, phosphoric, nitric, acetic, propionic,        succinic, glycolic, stearic, lactic, malic, tartaric, citric,        ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,        benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,        toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,        isethionic, and the like;    -   5.2 Compounds of Formulas I-IV et seq., wherein the salt is        fumaric acid addition salt;    -   5.3 Compounds of Formulas I-IV et seq., wherein the salt is        phosphoric acid addition salt;    -   5.4 Compounds of Formulas I-IV et seq., wherein the salt is a        toluenesulfonic acid addition salt;    -   5.5 Any of 5.1-5.4 wherein the salt is in solid form.

In a sixth aspect, the present disclosure provides a pharmaceuticalcomposition (Pharmaceutical Composition 6) comprising a compoundaccording to any one of Compound I or 1.1-1.30, Compound II or 2.1-2.12,Compound III or 3.1-3.11, or Compound IV or 4.1-4.11 (collectively,Compounds of Formulas I-IV et seq. or compounds of the disclosure),e.g., in admixture with a pharmaceutically acceptable diluent orcarrier. The present disclosure provides additional exemplaryembodiments of Pharmaceutical Composition 6, including:

-   -   6.1 Pharmaceutical Composition 6, comprising Compound I or any        of 1.1-1.30;    -   6.2 Pharmaceutical Composition 6, comprising Compound II or any        of 2.1-2.12;    -   6.3 Pharmaceutical Composition 6, comprising Compound III or any        of 3.1-3.11;    -   6.4 Pharmaceutical Composition 6, comprising Compound IV or any        of 4.1-4.11;    -   6.5 Pharmaceutical Composition 6 or any of 6.1-6.4, wherein the        Compound of Formula I-IV et seq. is in solid form;    -   6.6 Pharmaceutical Composition 6 or any of 6.1-6.5, wherein the        Compound of Formulas I-IV et seq. is in pharmaceutically        acceptable salt form as described in Compounds 5.1-5.5;    -   6.7 Pharmaceutical Composition 6 or any of 6.1-6.6, wherein the        Compound of Formulas I-IV et seq. is in admixture with a        pharmaceutically acceptable diluent or carrier.

In a preferred embodiment, the Pharmaceutical Composition of the presentdisclosure comprises a Compound of Formula II-A, II-B, or II-C, in freeor pharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier. In another preferredembodiment, the Pharmaceutical Composition of the present disclosurecomprises a Compound of Formula III-A, III-B or III-C in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier. In another preferredembodiment, the Pharmaceutical Composition of the present disclosurecomprises a Compound of Formula IV-A, IV-B or IV-C in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier.

In a further embodiment, the Pharmaceutical Compositions of the presentdisclosure, are for a sustained or delayed release, e.g., depot,formulation. In one embodiment, the depot formulation (Depot Formulation6.8) is the Pharmaceutical Composition of any of 6.1-6.7, preferably infree or pharmaceutically acceptable salt form, and preferably inadmixture with a pharmaceutically acceptable diluent or carrier, e.g.,providing sustained or delayed release as an injectable depot.

In a further embodiment, the Depot Composition (Depot Composition 6.9)comprises Pharmaceutical Composition of any of 6.1-6.7, wherein R₁ is a—C(O)—C₆₋₁₅alkyl, in free or pharmaceutically acceptable salt form, inadmixture with a pharmaceutically acceptable diluent or carrier.

In another aspect, the present disclosure provides PharmaceuticalComposition 6.10, which is Pharmaceutical Composition 6 or any of6.1-6.9, wherein the Compound of Formulas I-IV et seq. is in a polymericmatrix. In one embodiment, the Compound of the present disclosure isdispersed or dissolved within the polymeric matrix. In a furtherembodiment, the polymeric matrix comprises standard polymers used indepot formulations such as polymers selected from a polyester of ahydroxyfatty acid and derivatives thereof, or a polymer of an alkylalpha-cyanoacrylate, a polyalkylene oxalate, a polyortho ester, apolycarbonate, a polyortho-carbonate, a polyamino acid, a hyaluronicacid ester, and mixtures thereof. In a further embodiment, the polymeris selected from a group consisting of polylactide, poly d,l-lactide,poly glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. Inanother embodiment, the polymer is selected form poly(glycolic acid),poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the foregoing,poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone,polydioxanone, poly(ortho carbonates), poly(acetals), poly(lacticacid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone),polyanhydrides, and natural polymers including albumin, casein, andwaxes, such as, glycerol mono- and distearate, and the like. In apreferred embodiment, the polymeric matrix comprisespoly(d,l-lactide-co-glycolide).

For example, in one embodiment of Pharmaceutical Composition 6.10, theCompound is the Compound of Formula I, wherein X is —NH— or —N(CH₃)— andY is —C(═O)— or —C(H)(OH)—, in free or pharmaceutically acceptable saltform. In another example of Pharmaceutical Composition 6.10, theCompound is the Compound of Formula II-A, II-B, or II-C, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable diluent or carrier. In another example ofPharmaceutical Composition 6.10, the Compound is the Compound of FormulaIII-A, III-B or III-C in free or pharmaceutically acceptable salt form,in admixture with a pharmaceutically acceptable diluent or carrier. Inanother example of Pharmaceutical Composition 6.10, the Compound is theCompound of Formula IV-A, IV-B or IV-C in free or pharmaceuticallyacceptable salt form, in admixture with a pharmaceutically acceptablediluent or carrier. In another embodiment of each of the foregoingexamples of Pharmaceutical Composition 6.10, the polymeric matrixcomprises a poly(d,l-lactide-co-glycolide).

The (Pharmaceutical) Compositions 6 and 6.1-6.10 are particularly usefulfor sustained or delayed release, wherein the Compound of the presentdisclosure is released upon degradation of the polymeric matrix. TheseCompositions may be formulated for controlled- and/or sustained-releaseof the Compounds of the present disclosure (e.g., as a depotcomposition) over a period of up to 180 days, e.g., from about 14 toabout 30 to about 180 days. For example, the polymeric matrix maydegrade and release the Compounds of the present disclosure over aperiod of about 30, about 60 or about 90 days. In another example, thepolymeric matrix may degrade and release the Compounds of the presentdisclosure over a period of about 120, or about 180 days.

In still another embodiment, the Pharmaceutical Compositions of thepresent disclosure, for example the depot composition of the presentdisclosure, e.g., Pharmaceutical Composition 6.10, is formulated foradministration by injection.

In a seventh aspect, the present disclosure provides the Compounds ofFormulas I-IV et seq. as hereinbefore described, in an osmoticcontrolled release oral delivery system (OROS), which is described in WO2000/35419 and EP 1 539 115 (U.S. Pub. No. 2009/0202631), the contentsof each of which applications are incorporated by reference in theirentirety. Therefore in one embodiment of the seventh aspect, the presentdisclosure provides a pharmaceutical composition or device comprising(a) a gelatin capsule containing a Compound of any of Formulae I-IV etseq. in free or pharmaceutically acceptable salt form or aPharmaceutical Composition of the Invention, as hereinbefore described;(b) a multilayer wall superposed on the gelatin capsule comprising, inoutward order from the capsule: (i) a barrier layer, (ii) an expandablelayer, and (iii) a semipermeable layer; and (c) and orifice formed orformable through the wall. (Composition P.1)

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a gelatin capsule containing a liquid, theCompound of Formulas I-IV et seq. in free or pharmaceutically acceptablesalt form or a Pharmaceutical Composition of the Invention, e.g., any ofPharmaceutical Composition 6 or 6.1-6.10, the gelatin capsule beingsurrounded by a composite wall comprising a barrier layer contacting theexternal surface of the gelatin capsule, an expandable layer contactingthe barrier layer, a semi-permeable layer encompassing the expandablelayer, and an exit orifice formed or formable in the wall. (CompositionP.2)

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the Compound of Formulas I-IV et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,e.g., any of Pharmaceutical Composition 6 or 6.1-6.10, the gelatincapsule being surrounded by a composite wall comprising a barrier layercontacting the external surface of the gelatin capsule, an expandablelayer contacting the barrier layer, a semipermeable layer encompassingthe expandable layer, and an exit orifice formed or formable in thewall, wherein the barrier layer forms a seal between the expandablelayer and the environment at the exit orifice. (Composition P.3)

In still another embodiment of the seventh aspect, the inventionprovides a composition comprising a gelatin capsule containing a liquid,the Compound of Formulas I-IV et seq. in free or pharmaceuticallyacceptable salt form or a Pharmaceutical Composition of the Invention,e.g., any of Pharmaceutical Composition 6 or 6.1-6.10, the gelatincapsule being surrounded by a barrier layer contacting the externalsurface of the gelatin capsule, an expandable layer contacting a portionof the barrier layer, a semi-permeable layer encompassing at least theexpandable layer, and an exit orifice formed or formable in the dosageform extending from the external surface of the gelatin capsule to theenvironment of use. (Composition P.4). The expandable layer may beformed in one or more discrete sections, such as for example, twosections located on opposing sides or ends of the gelatin capsule.

In a particular embodiment of the seventh aspect, the Compound of thepresent disclosure in the Osmotic-controlled Release Oral deliverySystem (i.e., in Composition P.1-P.4) is in a liquid formulation, whichformulation may be neat, liquid active agent, liquid active agent in asolution, suspension, emulsion or self-emulsifying composition or thelike.

Further information on Osmotic-controlled Release Oral delivery Systemcomposition including characteristics of the gelatin capsule, barrierlayer, an expandable layer, a semi-permeable layer; and orifice may befound in WO 2000/35419, the contents of which are incorporated byreference in their entirety.

Other Osmotic-controlled Release Oral delivery System for the Compoundof Formulas I-IV et seq. or the Pharmaceutical Composition of thepresent disclosure may be found in EP 1 539 115 (U.S. Pub. No.2009/0202631), the contents of which are incorporated by reference intheir entirety. Therefore, in another embodiment of the seventh aspect,the invention provides a composition or device comprising (a) two ormore layers, said two or more layers comprising a first layer and asecond layer, said first layer comprises the Compound of Formulas I-IVet seq., in free or pharmaceutically acceptable salt form, or aPharmaceutical Composition as herein before described said second layercomprises a polymer; (b) an outer wall surrounding said two or morelayers; and (c) an orifice in said outer wall. (Composition P.5)

Composition P.5 preferably utilizes a semi-permeable membranesurrounding a three-layer-core: in these embodiments the first layer isreferred to as a first drug layer and contains low amounts of drug(e.g., the Compound of Formulas I-IV et seq.) and an osmotic agent suchas salt, the middle layer referred to as the second drug layer containshigher amounts of drug, excipients and no salt; and the third layerreferred to as the push layer contains osmotic agents and no drug. Atleast one orifice is drilled through the membrane on the first druglayer end of the capsule-shaped tablet. (Composition P.6)

Composition P.5 or P.6 may comprise a membrane defining a compartment,the membrane surrounding an inner protective subcoat, at least one exitorifice formed or formable therein and at least a portion of themembrane being semi-permeable; an expandable layer located within thecompartment remote from the exit orifice and in fluid communication withthe semi-permeable portion of the membrane; a first drug layer locatedadjacent the exit orifice; and a second drug layer located within thecompartment between the first drug layer and the expandable layer, thedrug layers comprising the Compound of the Invention in free orpharmaceutically acceptable salt thereof. Depending upon the relativeviscosity of the first drug layer and second drug layer, differentrelease profiles are obtained. It is imperative to identify the optimumviscosity for each layer. In the present invention, viscosity ismodulated by addition of salt, sodium chloride. The delivery profilefrom the core is dependent on the weight, formulation and thickness ofeach of the drug layers. (Composition P.7)

In a particular embodiment, the invention provides Composition P.7wherein the first drug layer comprising salt and the second drug layercontaining no salt. Composition P.5-P.7 may optionally comprise aflow-promoting layer between the membrane and the drug layers.

Compositions P.1-P.7 will generally be referred to as Osmotic-controlledRelease Oral delivery System Composition.

In an eighth aspect, the invention provides a method (Method 1) for thetreatment or prophylaxis of a central nervous system disorder,comprising administering to a patient in need thereof a Compound ofFormulas I-IV et seq. or a Pharmaceutical Composition 6 or 6.1-6.10 orP.1-P.7, for example Method 1 wherein the compound or compositionadministered is:

-   -   1.1 Compound I or any of 1.1-1.30, in free or pharmaceutically        acceptable salt form;    -   1.2 Compound II or any of 2.1-2.12, in free or pharmaceutically        acceptable salt form;    -   1.3 Compound III or any of 3.1-3.11, in free or pharmaceutically        acceptable salt form;    -   1.4 Compound IV or any of 4.1-4.11, in free or pharmaceutically        acceptable salt form;    -   1.5 The Compounds of Embodiment 5 or any of 5.1-5.5; 1.6        Compound of Formula II-A, II-B, or II-C in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   1.7 Compound of Formula III-A, III-B or III-C, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   1.8 Compound of Formula IV-A, IV-B or IV-C, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   1.9 a Pharmaceutical Composition as described by any of        Compositions 6 and 6.1-6.10;    -   1.10 a Pharmaceutical Composition comprising a Compound of        Formula II-A, II-B, or II-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   1.11 a Pharmaceutical Composition comprising a Compound of        Formula III-A, III-B or III-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   1.12 a Pharmaceutical Composition comprising a Compound of        Formula IV-A, IV-B or IV-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   1.13 Depot Composition as described in Depot Composition 6.09 or        6.10;    -   1.14 Pharmaceutical Composition P.1-P.7;    -   1.15 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described;

In a further embodiment of the eighth aspect, the present disclosureprovides Method 1 or any of Methods 1.1-1.15, wherein the method isfurther as described as follows:

-   -   1.16 Method 1 or any of Methods 1.1-1.15, wherein the central        nervous system disorder is a disorder selected from a group        consisting of obesity, anxiety, depression (for example        refractory depression and MDD), psychosis (including psychosis        associated with dementia, such as hallucinations in advanced        Parkinson's disease or paranoid delusions), schizophrenia, sleep        disorders (particularly sleep disorders associated with        schizophrenia and other psychiatric and neurological diseases),        sexual disorders, migraine, conditions associated with cephalic        pain, social phobias, agitation in dementia (e.g., agitation in        Alzheimer's disease), agitation in autism and related autistic        disorders, gastrointestinal disorders such as dysfunction of the        gastrointestinal tract motility, and dementia, for example        dementia of Alzheimer's disease or of Parkinson's disease; mood        disorders; and drug dependencies, for example, opiate dependency        and/or alcohol dependency, or withdrawal from drug or alcohol        dependency (e.g., opiate dependency); or binge eating disorder;    -   1.17 Method 1 or any of Methods 1.1-1.16, wherein the central        nervous system disorder is a disorder involving serotonin        5-HT₂A, dopamine D2 receptor system and/or serotonin reuptake        transporter (SERT) pathways as similarly described in        WO/2009/145900, the contents of which are herein incorporated by        reference in their entirety;    -   1.18 Method 1 or any of Methods 1.1-1.17, wherein the central        nervous system disorder is a disorder involving the μ-opioid        receptor;    -   1.19 Method 1 or any of Methods 1.1-1.18, wherein the central        nervous system disorder is a disorder selected from the        following: (i) psychosis, e.g., schizophrenia, in a patient        suffering from depression; (2) depression in a patient suffering        from psychosis, e.g., schizophrenia; (3) mood disorders        associated with psychosis, e.g., schizophrenia or Parkinson's        disease; (4) sleep disorders associated with psychosis, e.g.,        schizophrenia or Parkinson's disease; and (5) substance        addiction, substance use disorders and/or substance-induced        disorders, optionally wherein the patient suffers from residual        symptoms of anxiety or anxiety disorder;    -   1.20 Method 1 or any of Methods 1.1-1.18, wherein the central        nervous system disorder is psychosis, e.g., schizophrenia and        said patient is a patient suffering from depression;    -   1.21 Method 1 or any of Methods 1.1-1.20, wherein said patient        is unable to tolerate the side effects of conventional        antipsychotic drugs, e.g., chlorpromazine, haloperidol,        droperidol, fluphenazine, loxapine, mesoridazine molindone,        perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone and        ziprasidone;    -   1.22 Method 1 or any of Methods 1.1-1.20, wherein said patient        is unable to tolerate the side effects of conventional        antipsychotic drugs, e.g., haloperidol, aripiprazole, clozapine,        olanzapine, quetiapine, risperidone, and ziprasidone;    -   1.23 Method 1 or any of Methods 1.1-1.22, wherein said disorder        is depression and said patient is a patient suffering from        psychosis, e.g., schizophrenia, or Parkinson's disease;    -   1.24 Method 1 or any of Methods 1.1-1.22, wherein said disorder        is sleep disorder and said patient is suffering from depression;    -   1.25 Method 1 or any of Methods 1.1-1.22, wherein said one or        more disorders is sleep disorder and said patient is suffering        from psychosis, e.g., schizophrenia;    -   1.26 Method 1 or any of Methods 1.1-1.22, wherein said one or        more disorders is sleep disorder and said patient is suffering        from Parkinson's disease;    -   1.27 Method 1 or any of Methods 1.1-1.22, wherein said one or        more disorders is sleep disorder and said patient is suffering        from depression and psychosis, e.g., schizophrenia, or        Parkinson's disease.    -   1.28 Method 1 or any of 1.1-1.27, wherein said patient is        suffering from a drug dependency disorder, optionally in        conjunction with any preceding disorders, for example, wherein        said patient suffers from opiate dependency and/or alcohol        dependency, or from withdrawal from drug or alcohol dependency,        optionally wherein the patient suffers from residual symptoms of        anxiety or anxiety disorder;    -   1.29 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg;    -   1.30 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day;    -   1.31 Any of the foregoing methods wherein a condition to be        treated is dyskinesia, e.g. in a patient receiving dopaminergic        medications, e.g., medications selected from levodopa and        levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B        inhibitors), dopamine agonists, and anticholinergics, e.g.,        levodopa;    -   1.32 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

Substance-use disorders and substance-induced disorders are the twocategories of substance-related disorders defined by the Fifth Editionof the DSM (the Diagnostic and Statistical Manual of Mental Disorders. Asubstance-use disorder is a pattern of symptoms resulting from use of asubstance which the individual continues to take, despite experiencingproblems as a result. A substance-induced disorder is a disorder inducedby use if the substance. Substance-induced disorders includeintoxication, withdrawal, substance induced mental disorders, includingsubstance induced psychosis, substance induced bipolar and relateddisorders, substance induced depressive disorders, substance inducedanxiety disorders, substance induced obsessive-compulsive and relateddisorders, substance induced sleep disorders, substance induced sexualdysfunctions, substance induced delirium and substance inducedneurocognitive disorders.

The DSM-V includes criteria for classifying a substance use disorder asmild, moderate or severe. In some embodiments of the methods disclosedherein, the substance use disorder is selected from a mild substance usedisorder, a moderate substance use disorder or a severe substance usedisorder. In some embodiments, the substance use disorder is a mildsubstance use disorder. In some embodiments, the substance use disorderis a moderate substance use disorder. In some embodiments, the substanceuse disorder is a severe substance use disorder.

Anxiety is a highly prevalent co-morbid disorder in patients undergoingtreatment of substance use or substance abuse. A common treatment forsubstance abuse disorder is the combination of the partial opioidagonist buprenorphine with the opioid antagonist naloxone, but neitherof these drugs has any significant effect on anxiety, thus leading tothe common result that a third drug, such as a benzodiazepine-classanxiolytic agent. This makes treatment regimens and patient compliancemore difficult. In contrast, the Compounds of the present disclosureprovide opiate antagonism along with serotonin antagonism and dopaminemodulation. This may result in significant enhancement of treatment ofpatients with substance use or abuse disorder concomitant with anxiety.Depression is also a highly prevalent disorder in patients undergoingsubstance use or substance abuse treatment. Thus, antidepressants, suchas SSRIs, are also often used concomitantly in patients undergoingsubstance abuse treatment. Compounds of the present disclosure may alsoenhance treatment in such patients by providing treatment for substanceuse or substance abuse as well as both anxiety and depression.

The compounds of the present disclosure may have anxiolytic propertiesameliorating the need for treatment of a patient with an anxiolyticagent where said patients suffers from co-morbid anxiety. Thus, in someembodiments, the present disclosure provides a method according toMethod 1, or any of Methods 1.1-1.32, wherein the central nervous systemdisorder is a substance addiction, substance use disorders and/orsubstance-induced disorders, or a substance abuse disorder, for example,in a patient suffering from symptoms of anxiety or who is diagnosed withanxiety as a co-morbid disorder, or as a residual disorder, wherein themethod does not comprise the further administration of an anxiolyticagent, such as a benzodiazepine. Benzodiazepines are GABA-modulatingcompounds, including those discussed with reference to Method 3.1 and3.2 below.

In another embodiment of the eighth aspect, the present disclosureprovides Method 1 or any of Methods 1.1-1.15, wherein the method isfurther as described as follows:

-   -   1.33 Method 1 or any of Methods 1.1-1.32, wherein the central        nervous system disorder is a disorder selected from        obsessive-compulsive disorder (OCD), obsessive-compulsive        personality disorder (OCPD), general anxiety disorder, social        anxiety disorder, panic disorder, agoraphobia, compulsive        gambling disorder, compulsive eating disorder, body dysmorphic        disorder, hypochondriasis, pathological grooming disorder,        kleptomania, pyromania, attention deficit-hyperactivity disorder        (ADHD), attention deficit disorder (ADD), impulse control        disorder, and related disorders, and combination thereof.    -   1.34 Method 1 or any one Method 1.1-1.33, wherein the central        nervous system disorder is selected from obsessive-compulsive        disorder (OCD), obsessive-compulsive personality disorder        (OCPD), social anxiety disorder, panic disorder, agoraphobia,        compulsive gambling disorder, compulsive eating disorder, body        dysmorphic disorder and impulse control disorder.    -   1.35 Method 1 or any one of Method 1.1-1.33, wherein the central        nervous system disorder is obsessive-compulsive disorder (OCD)        or obsessive-compulsive personality disorder (OCPD).    -   1.36 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with selective serotonin reuptake inhibitors (SSRIs),        such as citalopram, escitalopram, fluoxetine, fluvoxamine,        paroxetine, and sertraline.    -   1.37 Any foregoing method, wherein said patient is not        responsive to or cannot tolerate the side effects from,        treatment with serotonin-norepinephrine reuptake inhibitors        (SNRIs), such as venlafaxine, sibutramine, duloxetine,        atomoxetine, desvenlafaxine, milnacipran, and levomilnacipran.    -   1.38. Any foregoing method, wherein said patient is not response        to or cannot tolerate the side effects from, treatment with        antipsychotic agents, such as clomipramine, risperidone,        quetiapine and olanzapine.    -   1.39 Method 1 or any of Method 1.1-1.33, wherein the central        nervous system disorder is a pain disorder, e.g., a condition        associated with pain, such as cephalic pain, idiopathic pain,        neuropathic pain, chronic pain (e.g., moderate to moderately        severe chronic pain, for example, in patients requiring 24-hour        extended treatment for other ailments), fibromyalgia, dental        pain, or chronic fatigue.    -   1.40 Any foregoing method, wherein the patient is not responsive        to or cannot tolerate the side effects of non-narcotic        analgesics and/or opiate and opioid drugs, or wherein the use of        opiate drugs are contraindicated in said patient, for example,        due to prior substance abuse or a high potential for substance        abuse, such as opiate and opioid drugs including, e.g.,        morphine, codeine, thebaine, oripavine, morphine dipropionate,        morphine dinicotinate, dihydrocodeine, buprenorphine, etorphine,        hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,        alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,        remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,        prodine, promedol, propoxyphene, dextropropoxyphene, methadone,        diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,        nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol,        and anileridine, or any combinations thereof;    -   1.41 Method I or any of Methods 1.1-1.40, wherein the central        nervous system disease or disorder is a drug dependency (for        example, opiate dependency, cocaine dependency, amphetamine        dependency, and/or alcohol dependency), or withdrawal from drug        or alcohol dependency (e.g., opiate, cocaine, or amphetamine        dependency), and optionally wherein the patient also suffers        from a co-morbidity, such as anxiety, depression or psychosis;    -   1.42 Any of the foregoing methods, wherein the effective amount        is 1 mg-1000 mg, preferably 2.5 mg-50 mg;    -   1.43 Any of the foregoing methods, wherein the effective amount        is 1 mg-100 mg per day, preferably 2.5 mg-50 mg per day.

In another embodiment, the present disclosure provides Method 1 or anyof Methods 1.1-1.32, or any of Methods 1.33-1.43, wherein the Compoundsof Formulas I-IV et seq. or Pharmaceutical Composition 6 or 6.1-6.10 orP.1-P.7 comprises:

-   -   1.44 a Compound of Formula II-A, II-B, II-C or II-D, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   1.45 a Compound of Formula III-A, III-B or III-C in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier; or    -   1.46 a Compound of Formula IV-A, IV-B or IV-C in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier

In still another embodiment, the present disclosure provides any of theMethods 1 or 1.1-1.46 as hereinbefore described wherein the disorder isschizophrenia or sleep disorder. In some embodiments, said schizophreniais associated with depression.

In still another embodiment, the present disclosure provides any ofMethods 1.1-1.46, wherein the Depot Composition of the Invention (e.g.,Depot Composition of any of formulae 6.8-6.10), or (Pharmaceutical)Composition 6 or 6.1-6.7, or Composition P.1-P.7, is administered forcontrolled- and/or sustained-release of the Compounds of the Inventionover a period of from about 14 days, about 30 to about 180 days,preferably over the period of about 30, about 60 or about 90 days.Controlled- and/or sustained-release is particularly useful forcircumventing premature discontinuation of therapy, particularly forantipsychotic drug therapy where non-compliance or non-adherence tomedication regimes is a common occurrence.

In still another embodiment, the invention provides any Method 1 or1.1-1.46 as hereinbefore described, wherein the Depot Composition of thepresent disclosure is administered for controlled- and/orsustained-release of the Compounds of the Invention over a period oftime.

In a ninth aspect, the invention provides a method (Method 2) for theprophylaxis or treatment of one or more sleep disorders comprisingadministering to a patient in need thereof a Compound of Formulas I-IVet seq. or a Pharmaceutical Composition 6 or 6.1-6.10 or P.1-P.7,(Method 2) for example Method 2 wherein the compound or compositionadministered is:

-   -   2.1 Compound I or 1.1-1.30, in free or pharmaceutically        acceptable salt form;    -   2.2 Compound II or 2.1-2.12, in free or pharmaceutically        acceptable salt form;    -   2.3 Compound III or 3.1-3.11, in free or pharmaceutically        acceptable salt form;    -   2.4 Compound IV or 4.1-4.11, in free or pharmaceutically        acceptable salt form;    -   2.5 Compound 5 or 5.1-5.5;    -   2.6 Compound of Formula II-A, II-B, II-C or II-D, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   2.7 Compound of Formula III-A, III-B or III-C, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   2.8 Compound of Formula IV-A, IV-B or IV-C, in free or        pharmaceutically acceptable salt form, in admixture with a        pharmaceutically acceptable diluent or carrier;    -   2.9 a Pharmaceutical Composition as described by any of        Compositions 6 and 6.1-6.10;    -   2.10 a Pharmaceutical Composition comprising a Compound of        Formula II-A, II-B, or II-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   2.11 a Pharmaceutical Composition comprising a Compound of        Formula III-A, III-B or III-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   2.12 a Pharmaceutical Composition comprising a Compound of        Formula IV-A, IV-B or IV-C, in free or pharmaceutically        acceptable salt form, in admixture with a pharmaceutically        acceptable diluent or carrier;    -   2.13 Depot Composition as described in Depot Composition 6.09 or        6.10;    -   2.14 Pharmaceutical Composition P.1-P.7;    -   2.15 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described;

In a further embodiment of the ninth aspect, the invention providesMethod 2, or 2.1-2.15, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed; for example:

-   -   2.16 Any of the foregoing methods, wherein the sleep disorder is        sleep maintenance insomnia;    -   2.17 Any of the foregoing methods, wherein the effective amount        is 1 mg-5 mg, preferably 2.5-5 mg, per day;    -   2.18 Any of the foregoing methods, wherein the effective amount        is 2.5 mg or 5 mg, per day;    -   2.19 Any of the foregoing methods wherein the sleep disorder is        in a patient suffering from or at risk of dyskinesia, e.g., a        patient receiving dopaminergic medications, e.g., selected from        levodopa and levodopa adjuncts (carbidopa, COMT inhibitors,        MAO-B inhibitors), dopamine agonists, and anticholinergics,        e.g., receiving levodopa;    -   2.20 Any of the foregoing methods wherein the patient suffers        from Parkinson's disease.

In a further embodiment of the ninth aspect, the invention providesMethod 2, or any of 2.1-2.20, wherein the sleep disorder includes sleepmaintenance insomnia, frequent awakenings, and waking up feelingunrefreshed.

The Compounds of the present disclosure, the Pharmaceutical Compositionsof the present disclosure or the Depot Compositions of the presentdisclosure may be used in combination with a second therapeutic agent,particularly at lower dosages than when the individual agents are usedas a monotherapy so as to enhance the therapeutic activities of thecombined agents without causing the undesirable side effects commonlyoccur in conventional monotherapy. Therefore, the Compounds of thepresent disclosure may be simultaneously, sequentially, orcontemporaneously administered with other anti-depressant,anti-psychotic, other hypnotic agents, and/or agents use to treatParkinson's disease or mood disorders. In another example, side effectsmay be reduced or minimized by administering a Compound of the presentdisclosure in combination with one or more second therapeutic agents infree or salt form, wherein the dosages of (i) the second therapeuticagent(s) or (ii) both Compound of the present disclosure and the secondtherapeutic agents, are lower than if the agents/compounds areadministered as a monotherapy. In a particular embodiment, the Compoundsof the present disclosure are useful to treat dyskinesia in a patientreceiving dopaminergic medications, e.g., selected from levodopa andlevodopa adjuncts (carbidopa, COMT inhibitors, MAO-B inhibitors),dopamine agonists, and anticholinergics, e.g., such as are used in thetreatment of Parkinson's disease.

Therefore, in a tenth aspect, the present disclosure provides Method I,or any of Methods 1.1-35, or Method 2 or any of 2.1-20, furthercomprising one or more therapeutic agents selected from compounds thatmodulate GABA activity (e.g., enhances the activity and facilitates GABAtransmission), a GABA-B agonist, a 5-HT receptor modulator (e.g., a5-HT_(1A) agonist, a 5-HT_(2A) antagonist, a 5-HT_(2A) inverse agonist,etc.), a melatonin receptor agonist, an ion channel modulator (e.g.,blocker), a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexinreceptor antagonist, an H3 agonist or antagonist, a noradrenergicagonist or antagonist, a galanin agonist, a CRH antagonist, human growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, aneurokinin-1 drug, an anti-depressant, and opiate agonist and/or partialopiate agonist, and an antipsychotic agent, e.g., an atypicalantipsychotic agent, in free or pharmaceutically acceptable salt form(Method I-A and II-A respectively; collectively, “Method 3”). In furtherembodiments of the tenth aspect, the present disclosure provides MethodI, or any of Methods 1.1-1.35, or Method 2 or any of 2.1-2.20, furthercomprising one or more therapeutic agents selected from the foregoingand further selected from agonists or partial agonists of the mu-opiate,kappa-opiate, delta-opiate, and/or nociceptin/orphanin receptors. Infurther embodiments of the tenth aspect, the present disclosure alsoprovides Method I, or any of Methods 1.1-35, or Method 2 or any of2.1-2.20, further comprising one or more therapeutic agents selectedfrom a serotonin HT6 receptor antagonist, and an mGluR-2, -3 or -5receptor agonist or antagonist (including both positive and negativemodulators and partial agonists).

In a further embodiment of the tenth aspect, the invention providesMethod I-A or II-A as follows, further comprising one or moretherapeutic agents.

-   -   3.1 Method I-A or II-A, wherein the therapeutic agent(s) is        compounds that modulate GABA activity (e.g., enhances the        activity and facilitates GABA transmission);    -   3.2 Method I-A or II-A or 3.1, wherein the GABA compound is        selected from a group consisting of one or more of doxepin,        alprazolam, bromazepam, clobazam, clonazepam, clorazepate,        diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,        nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals) and estazolam;    -   3.3 Method I-A or II-A, wherein the therapeutic agent is an        additional 5HT2a antagonist;    -   3.4 Method I-A or II-A or 3.3, wherein said additional 5HT2a        antagonist is selected from one or more of ketanserin,        risperidone, eplivanserin, volinanserin (Sanofi-Aventis,        France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HY        10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego,        Calif.), and AVE8488 (Sanofi-Aventis, France);    -   3.5 Method I-A or II-A, wherein the therapeutic agent is a        melatonin receptor agonist;    -   3.6 Method I-A or II-A or 3.5, wherein the melatonin receptor        agonist is selected from a group consisting of one or more of        melatonin, ramelteon (ROZEREM®, Takeda Pharmaceuticals, Japan),        VEC-162 (Vanda Pharmaceuticals, Rockville, Md.), PD-6735 (Phase        II Discovery) and agomelatine;    -   3.7 Method I-A or II-A, wherein the therapeutic agent is an ion        channel blocker;    -   3.8 Method I-A or II-A or 3.7, wherein said ion channel blocker        is one or more of lamotrigine, gabapentin and pregabalin.    -   3.9 Method I-A or II-A, wherein the therapeutic agent is an        orexin receptor antagonist;    -   3.10 Method I-A or II-A or 3.9, wherein the orexin receptor        antagonist is selected from a group consisting of orexin, a        1,3-biarylurea, SB-334867-a (GlaxoSmithKline, UK), GW649868        (GlaxoSmithKline) and a benzamide derivative;    -   3.11 Method I-A or II-A, wherein the therapeutic agent is the        serotonin-2 antagonist/reuptake inhibitor (SARI);    -   3.12 Method I-A or II-A or 3.11, wherein the serotonin-2        antagonist/reuptake inhibitor (SARI) is selected from a group        consisting of one or more Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone and trazodone;    -   3.13 Method I-A or II-A, wherein the therapeutic agent is the        5HTIa agonist;    -   3.14 Method I-A or II-A or 3.13, wherein the 5HTIa agonist is        selected from a group consisting of one or more of repinotan,        sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San        Diego, Calif.);    -   3.15 Method I-A or II-A, wherein the therapeutic agent is the        neurokinin-1 drug;    -   3.16 Method I-A or II-A or 3.15, wherein the neurokinin-1 drug        is Casopitant (GlaxoSmithKline);    -   3.17 Method I-A or II-A, wherein the therapeutic agent is an        antipsychotic agent;    -   3.18 Method I-A or II-A or 3.17, wherein the antipsychotic agent        is selected from a group consisting of chlorpromazine,        haloperidol, droperidol, fluphenazine, loxapine, mesoridazine,        molindone, perphenazine, pimozide, prochlorperazine promazine,        thioridazine, thiothixene, trifluoperazine, clozapine,        aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone        and paliperidone;    -   3.19 Method I-A or II-A, wherein the therapeutic agent is an        anti-depressant;    -   3.20 Method I-A or II-A or 3.19, wherein the anti-depressant is        selected from amitriptyline, amoxapine, bupropion, citalopram,        clomipramine, desipramine, doxepin, duloxetine, escitalopram,        fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,        mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine        sulfate, protriptyline, sertraline, tranylcypromine, trazodone,        trimipramine, and venlafaxine;    -   3.21 Method I-A or II-A, 3.17 or 3.18, wherein the antipsychotic        agent is an atypical antipsychotic agent;    -   3.22 Method I-A or II-A, or any of 3.17-3.21, wherein the        atypical antipsychotic agent is selected from a group consisting        of clozapine, aripiprazole, olanzapine, quetiapine, risperidone,        ziprasidone, and paliperidone;    -   3.23 Method I-A or II-A, wherein the therapeutic agent is        selected from any of methods 3.1-3.22, e.g., selected from a        group consisting of modafinil, armodafinil, doxepin, alprazolam,        bromazepam, clobazam, clonazepam, clorazepate, diazepam,        flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,        oxazepam, temazepam, triazolam, indiplon, zopiclone,        eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,        tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,        ketanserin, risperidone, eplivanserin, volinanserin        (Sanofi-Aventis, France), pruvanserin, MDL 100907        (Sanofi-Aventis, France), HY 10275 (Eli Lilly), APD 125 (Arena        Pharmaceuticals, San Diego, Calif.), AVE8488 (Sanofi-Aventis,        France), repinotan, sarizotan, eptapirone, buspirone, MN-305        (MediciNova, San Diego, Calif.), melatonin, ramelteon (ROZEREM®,        Takeda Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals,        Rockville, Md.), PD-6735 (Phase II Discovery), agomelatine,        lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea,        SB-334867-a (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a        benzamide derivative, Org 50081 (Organon-Netherlands),        ritanserin, nefazodone, serzone, trazodone, Casopitant        (GlaxoSmithKline), amitriptyline, amoxapine, bupropion,        citalopram, clomipramine, desipramine, doxepin, duloxetine,        escitalopram, fluoxetine, fluvoxamine, imipramine,        isocarboxazid, maprotiline, mirtazapine, nefazodone,        nortriptyline, paroxetine, phenelzine sulfate, protriptyline,        sertraline, tranylcypromine, trazodone, trimipramine,        venlafaxine, chlorpromazine, haloperidol, droperidol,        fluphenazine, loxapine, mesoridazine, molindone, perphenazine,        pimozide, prochlorperazine promazine, thioridazine, thiothixene,        trifluoperazine, clozapine, aripiprazole, olanzapine,        quetiapine, risperidone, ziprasidone and paliperidone;    -   3.24 Method I-A or II-A wherein the therapeutic agent is an H3        agonist;    -   3.25 Method I-A or II-A, wherein the therapeutic agent is an H3        antagonist;    -   3.26 Method I-A or II-A, wherein the therapeutic agent is a        noradrenergic agonist or antagonist;    -   3.27 Method I-A or II-A, wherein the therapeutic agent is a        galanin agonist;    -   3.28 Method I-A or II-A, wherein the therapeutic agent is a CRH        antagonist;    -   3.29 Method I-A or II-A, wherein the therapeutic agent is a        human growth hormone;    -   3.30 Method I-A or II-A, wherein the therapeutic agent is a        growth hormone agonist;    -   3.31 Method I-A or II-A, wherein the therapeutic agent is        estrogen;    -   3.32 Method I-A or II-A, wherein the therapeutic agent is an        estrogen agonist;    -   3.33 Method I-A or II-A, wherein the therapeutic agent is a        neurokinin-1 drug;    -   3.34 Method I-A or II-A, wherein a therapeutic agent is combined        with compounds of Formula (I) and the therapeutic agent is an        anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,        stalevo, Symmetrel, benztropine, biperiden, bromocriptine,        entacapone, pergolide, pramipexole, procyclidine, ropinirole,        selegiline and tolcapone;    -   3.35 Method I-A or II-A, wherein the therapeutic agent is an        opiate agonist or partial opiate agonist, for example, a        mu-agonist or partial agonist, or a kappa-agonist or partial        agonist, including mixed agonist/antagonists (e.g., an agent        with partial mu-agonist activity and kappa-antagonist activity);    -   3.36 Method 3.35, wherein the therapeutic agent is        buprenorphine, optionally, wherein said method does not include        co-treatment with an anxiolytic agent, e.g., a GABA compound or        benzodiazepine;    -   3.37 Method I-A or II-A, wherein compounds of Formula (I) may be        used to treat sleep disorders, depression, psychosis, or any        combinations thereof, in patients suffering from the listed        diseases and/or Parkinson's disease;    -   3.38 Method I-A or II-A, wherein the disorder is selected from        at least one or more of psychosis, e.g., schizophrenia,        depression, mood disorders, sleep disorders (e.g., sleep        maintenance and/or sleep onset) or any combination of disorders        thereof;    -   3.39 Any of the foregoing methods wherein the disorder is sleep        disorder;    -   3.40 Any of the foregoing methods, wherein the disorder is sleep        disorder associated with psychosis, e.g., schizophrenia or        Parkinson's disease; in free or pharmaceutically acceptable salt        form.

In an eleventh aspect of the invention, the combination of a Compound ofthe present disclosure and one or more second therapeutic agents asdescribed in Methods I-A, II-A or any of Methods 3 or 3.1-3.40 may beadministered as a Pharmaceutical Composition or a depot Composition ashereinbefore described. The combination compositions can includemixtures of the combined drugs, as well as two or more separatecompositions of the drugs, which individual compositions can be, forexample, co-administered together to a patient.

In a particular embodiment, Methods I-A, II-A, 3 or 3.1-3.40 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination with an atypical antipsychotic agent, e.g., a compoundselected from clozapine, aripiprazole, olanzapine, quetiapine,risperidone, ziprasidone, or paliperidone, in free or pharmaceuticallyacceptable salt form, for example wherein the dosage of the atypicalantipsychotic agent is reduced and/or side effects are reduced.

In another embodiment, Methods I-A, II-A, 3 or 3.1-3.40 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination with an anti-depressant, e.g., amitriptyline, amoxapine,bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine,escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid,maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine,phenelzine sulfate, protriptyline, sertraline, tranylcypromine,trazodone, trimipramine, or venlafaxine, in free or pharmaceuticallyacceptable salt form. Alternatively, the anti-depressant may be used asan adjunct medication in addition to the compound of the Invention.

In still another embodiment, Methods I-A, II-A, 3 or 3.1-3.40 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination with a compound that modulates GABA activity, e.g., acompound selected from doxepin, alprazolam, bromazepam, clobazam,clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam,midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon,zopiclone, eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin,tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam or anycombinations thereof, in free or pharmaceutically acceptable salt form.In other embodiments, the methods disclosed herein do not furthercomprise administration of an GABA compound, a benzodiazepine or anyother anxiolytic agent.

In another preferred embodiment, Methods I-A, II-A, 3 or 3.1-3.40comprises administering to a patient in need thereof, a Compound of theInvention in combination with doxepin in free or pharmaceuticallyacceptable salt form. Dosages of doxepin can vary in any range known toa person of ordinary skill in the art. In one example, a 10 mg dose ofdoxepin may be combined with any dosage of a compound of the Invention.

In another embodiment, Methods I-A, II-A, 3 or 3.1-3.40 comprisesadministering to a patient in need thereof, a Compound of the Inventionin combination (including as part of a daily dosage regimen) with anatypical stimulant, e.g., a modafinil, adrafinil, or armodafinil. Aregimen incorporating a Compound of the Invention with such drugspromotes more regular sleep, and avoids side effects such as psychosisor mania associated with higher levels of such drugs, e.g., in thetreatment of bipolar depression, cognition associated withschizophrenia, and excessive sleepiness and fatigue in conditions suchas Parkinson's disease and cancer.

In some embodiments of each of the Compounds of Formulas I-IV et seq.;Pharmaceutical Compositions 6 and 6.1-6.8; Depo Compositions 6.9 and6.10; Compositions P.1-P.7; Methods 1 and 1.1-1.46; and Methods 2 and2.1-2.20; the compound of the present disclosure is substantially freeof compound of Formula A.

In a twelfth aspect, the invention provides use of a compound asdescribed in the following:

-   -   11.1 Compound I or 1.1-1.30, in free or pharmaceutically        acceptable salt form;    -   11.2 Compound II or 2.1-2.12, in free or pharmaceutically        acceptable salt form;    -   11.3 Compound III or 3.1-3.11, in free or pharmaceutically        acceptable salt form;    -   11.4 Compound IV or 4.1-4.11, in free or pharmaceutically        acceptable salt form;    -   11.5 Compound 5 or 5.1-5.5;    -   11.6 a Compound of Formula II-A, II-B, II-C, II-D, or II-E in        free or pharmaceutically acceptable salt form;    -   11.7 a Compound of Formula III-A, III-B or III-C, in free or        pharmaceutically acceptable salt form;    -   11.8 a Compound of Formula IV-A, IV-B or IV-C, in free or        pharmaceutically acceptable salt form;    -   11.9 Pharmaceutical Composition 6 and 6.1-6.10;    -   11.10 Pharmaceutical Composition P.1-P.7;    -   11.11 Osmotic-controlled Release Oral delivery System        Composition as hereinbefore described;        (in the manufacture of a medicament) for the treatment or        prophylaxis of one or more disorders as disclosed hereinbefore,        e.g., in any of Method 1 or 1.1-1.46, any of Method 2 and        2.1-2.20, and Method 3 or 3.3-3.40, or any methods described in        the eleventh aspect of the invention.

In the thirteenth aspect, the invention provides a pharmaceuticalcomposition as hereinbefore described, e.g.:

-   -   12.1 Pharmaceutical Composition 6 and 6.1-6.10;    -   12.2 Pharmaceutical Composition P.1-P.7;    -   12.3 Osmotic-controlled Release Oral delivery System Composition        as hereinbefore described,

for use in the treatment or prophylaxis of one or more disorders asdisclosed hereinbefore, e.g., in any of Methods 1 and 1.1-1.46, Methods2 and 2.1-2.20, Methods I-A, II-A, 3 or 3.1-3.40 or any methodsdescribed in the eleventh or twelfth aspect of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mu-receptor antagonist activity of the compound ofExample 3 compared to naloxone, as described in Example 10.

FIG. 2 shows the mu-receptor agonist activity of the compounds ofExamples 1 and 3 compared to DAMGO and buprenorphine, as described inExample 10.

DETAILED DESCRIPTION OF THE INVENTION

If not otherwise specified or clear from context, the following terms asused herein have the following meetings:

“Alkyl” as used herein is a saturated or unsaturated hydrocarbon moiety,e.g., one to twenty-one carbon atoms in length, which may be linear orbranched (e.g., n-butyl or tert-butyl), preferably linear, unlessotherwise specified. For example, “C₁₋₂₁ alkyl” denotes alkyl having 1to 21 carbon atoms. In one embodiment, alkyl is optionally substitutedwith one or more hydroxy or C₁₋₂₂ alkoxy (e.g., ethoxy) groups. Inanother embodiment, alkyl contains 1 to 21 carbon atoms, preferablystraight chain and optionally saturated or unsaturated, for example insome embodiments wherein R₁ is an alkyl chain containing 1 to 21 carbonatoms, preferably 6-15 carbon atoms, 16-21 carbon atoms, e.g., so thattogether with the —C(O)— to which it attaches, e.g., when cleaved fromthe compound of Formula I, forms the residue of a natural or unnatural,saturated or unsaturated fatty acid.

The term “pharmaceutically acceptable diluent or carrier” is intended tomean diluents and carriers that are useful in pharmaceuticalpreparations, and that are free of substances that are allergenic,pyrogenic or pathogenic, and that are known to potentially cause orpromote illness. Pharmaceutically acceptable diluents or carriers thusexclude bodily fluids such as example blood, urine, spinal fluid,saliva, and the like, as well as their constituent components such asblood cells and circulating proteins. Suitable pharmaceuticallyacceptable diluents and carriers can be found in any of severalwell-known treatises on pharmaceutical formulations, for exampleAnderson, Philip O.; Knoben, James E.; Troutman, William G, eds.,Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Prattand Taylor, eds., Principles of Drug Action, Third Edition, ChurchillLivingston, N.Y., 1990; Katzung, ed., Basic and Clinical Pharmacology,Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., ThePharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001;Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams &Wilkins., 2000; and Martindale, The Extra Pharmacopoeia, Thirty-SecondEdition (The Pharmaceutical Press, London, 1999); all of which areincorporated by reference herein in their entirety.

The terms “purified,” “in purified form” or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process (e.g., from a reaction mixture),or natural source or combination thereof. Thus, the term “purified,” “inpurified form” or “in isolated and purified form” for a compound refersto the physical state of said compound after being obtained from apurification process or processes described herein or well known to theskilled artisan (e.g., chromatography, recrystallization, LC-MS andLC-MS/MS techniques and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell known to the skilled artisan.

The Compounds of Formula I, wherein Z is —(C═O)— or —(CH(OH))—,including for example the Compounds of Formulae II-B and II-C, may beproduced as metabolites of a compound of Formula A, and/or asmetabolites of a compound of Formula B:

The compound of Formula A is known to provide effective treatment of5-HT_(2A), SERT and/or D₂ receptor related disorders without significantextrapyramidal side effects, as similarly disclosed and claimed in WO2009/145900, the contents of which are incorporated by reference intheir entirety. The plasma levels of compounds of Formulas II-B and II-Cproduced from metabolism of a compound of Formula A are, however, quitelow and probably do not contribute significantly to the therapeuticactivity of the compound of Formula A. Compounds of Formulae II-D andII-E could also be present as metabolites, although this has so far notbeen detected. The Compounds of Formula I have unexpectedly been foundto have activity as antagonists of the μ-opioid receptor. This isunexpected because the compound of Formula A has not been know orunderstood to have any μ-opioid receptor activity or binding. Compoundsof Formula I wherein X is —NH— and wherein L is —O— are shown to haveparticularly good μ-opioid receptor antagonism. Such Compounds ofFormula I may therefore be useful in the treatment of drug dependency,such as opiate dependency and/or alcohol dependency, by inhibiting theendogenous opiate response to illicit drug administration, as well as byinhibiting the direct effects of ingestion of illicit opiate drugs.

It is surprising that metabolites of a compound of Formula A havesomewhat different relative receptor binding affinity that compounds ofFormula A. For example, the receptor binding profile of the compound forFormula II-B is very unique, with a combination of antagonist activitiesat 5-HT_(2A), D₁ and Mu opiate receptors, making this compound veryinteresting for treating mood disorders. The compound of Formula A isnot active at the Mu opiate receptor, for example.

Unless otherwise indicated, the Compounds of the present disclosure,e.g., Compound I or 1.1-1.30, Compound II or 2.1-2.18, Compound III or3.1-3.13, or Compound IV or 4.1-4.13 (collectively, Compounds ofFormulas I-IV et seq.) may exist in free or salt, e.g., as acid additionsalts, form. An acid-addition salt of a compound of the invention whichis sufficiently basic, for example, an acid-addition salt with, forexample, an inorganic or organic acid, for example hydrochloric,hydrobromic, sulphuric, phosphoric, acid acetic, trifluoroacetic,citric, maleic acid, toluene sulfonic, propionic, succinic, glycolic,stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic acid, and the like. In addition a salt ofa compound of the invention which is sufficiently acidic is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically-acceptablecation, for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)-amine.In a particular embodiment, the salt of the Compounds of the Inventionis a toluenesulfonic acid addition salt. In another particularembodiment, the salt of the Compounds of the Invention is a fumaric acidaddition salt. In a particular embodiment, the salt of the Compounds ofthe Invention is a phosphoric acid addition salt.

The Compounds of the present disclosure are intended for use aspharmaceuticals, therefore pharmaceutically acceptable salts arepreferred. Salts which are unsuitable for pharmaceutical uses may beuseful, for example, for the isolation or purification of free Compoundsof the Invention, and are therefore also included.

The Compounds of the present disclosure may comprise one or more chiralcarbon atoms. The compounds thus exist in individual isomeric, e.g.,enantiomeric or diastereomeric form or as mixtures of individual forms,e.g., racemic/diastereomeric mixtures. Any isomer may be present inwhich the asymmetric center is in the (R)-, (S)-, or(R,S)-configuration. The invention is to be understood as embracing bothindividual optically active isomers as well as mixtures (e.g.,racemic/diastereomeric mixtures) thereof. Accordingly, the Compounds ofthe Invention may be a racemic mixture or it may be predominantly, e.g.,in pure, or substantially pure, isomeric form, e.g., greater than 70%enantiomeric/diastereomeric excess (“ee”), preferably greater than 80%ee, more preferably greater than 90% ee, most preferably greater than95% ee. The purification of said isomers and the separation of saidisomeric mixtures may be accomplished by standard techniques known inthe art (e.g., column chromatography, preparative TLC, preparative HPLC,simulated moving bed and the like).

Geometric isomers by nature of substituents about a double bond or aring may be present in cis (Z) or trans (E) form, and both isomericforms are encompassed within the scope of this invention.

It is also intended that the compounds of the present disclosureencompass their stable and unstable isotopes. Stable isotopes arenonradioactive isotopes which contain one additional neutron compared tothe abundant nuclides of the same species (i.e., element). It isexpected that the activity of compounds comprising such isotopes wouldbe retained, and such compound would also have utility for measuringpharmacokinetics of the non-isotopic analogs. For example, the hydrogenatom at a certain position on the compounds of the disclosure may bereplaced with deuterium (a stable isotope which is non-radioactive).Examples of known stable isotopes include, but not limited to,deuterium, ¹³C, ¹⁵N, ¹⁸O. Alternatively, unstable isotopes, which areradioactive isotopes which contain additional neutrons compared to theabundant nuclides of the same species (i.e., element), e.g., ¹²³I, ¹³¹I,¹²⁵I, ¹¹C, ¹⁸F, may replace the corresponding abundant species of I, Cand F. Another example of useful isotope of the compound of theinvention is the ¹¹C isotope. These radio isotopes are useful forradio-imaging and/or pharmacokinetic studies of the compounds of theinvention. In addition, the substitution of atoms of having the naturalisotopic distributing with heavier isotopes can result in desirablechange in pharmacokinetic rates when these substitutions are made atmetabolically liable sites. For example, the incorporation of deuterium(²H) in place of hydrogen can slow metabolic degradation when theposition of the hydrogen is a site of enzymatic or metabolic activity.

In addition to the unique characteristic of the Compounds of the presentdisclosure, the Compounds of Formula I, wherein Y is —C(H)(OH)— may alsobe esterified to form physiologically hydrolysable and acceptable esterprodrugs. As used herein, “physiologically hydrolysable and acceptableesters” means esters of Compounds of the present disclosure which arehydrolysable under physiological conditions to yield hydroxy on the onehand and acid, e.g., carboxylic acid on the other, which are themselvesphysiologically tolerable at doses to be administered. For Example, theCompound of Formula I or Formula II wherein Y is —C(H)(OH) may beesterified to form a prodrug, i.e., a Compound of Formula I Formula IIwherein R₁ is —C(O)—C₁₋₂₁ alkyl. In some preferred embodiments, R₁ is—C(O)—C₁₋₂₁ alkyl, e.g., acyl acid esters, e.g., heptanoic, octanoic,decanoic, dodecanoic, tetradecanoic or hexadecanoic acid ester.

Similarly, wherein the Compounds of the present disclosure contain anamine group, prodrug of such amine, e.g., methyl amine prodrugs may alsoexist wherein the prodrug is cleaved to release the amine metabolite invivo following administration.

The prodrugs of the Compounds of the present disclosure wherein R₁ is—C(O)—C₁₋₂₁alkyl, preferably —C₆₋₂₁alkyl, more preferably C₆₋₁₅ alkyl,more preferably linear, saturated or unsaturated and optionallysubstituted with one or more hydroxy or alkoxy groups, are particularlyuseful for sustained- and/or delayed release so as to achieve a longacting effect, e.g., wherein the Compounds of the present disclosure isreleased over a period of from about 14 to about 30 to about 180 days,preferably over about 30 or about 60 or about 90 days, for example asdescribed in any of depot composition as described herein. Preferably,the sustained and/or delayed-release formulation is an injectableformulation.

Alternatively and/or additionally, the Compounds of the presentdisclosure may be included as a depot formulation, e.g., by dispersing,dissolving or encapsulating the Compounds of the Invention in apolymeric matrix as described in any of Composition 6 and 6.1-6.10, suchthat the Compound is continually released as the polymer degrades overtime. The release of the Compounds of the Invention from the polymericmatrix provides for the controlled- and/or delayed- and/orsustained-release of the Compounds, e.g., from the pharmaceutical depotcomposition, into a subject, for example a warm-blooded animal such asman, to which the pharmaceutical depot is administered. Thus, thepharmaceutical depot delivers the Compounds of the Invention to thesubject at concentrations effective for treatment of the particulardisease or medical condition over a sustained period of time, e.g.,14-180 days, preferably about 30, about 60 or about 90 days.

Polymers useful for the polymeric matrix in the Composition of theInvention (e.g., Depot composition of the Invention) may include apolyester of a hydroxyfatty acid and derivatives thereof or other agentssuch as polylactic acid, polyglycolic acid, polycitric acid, polymalicacid, poly-beta.-hydroxybutyric acid, epsilon.-capro-lactone ringopening polymer, lactic acid-glycolic acid copolymer, 2-hydroxybutyricacid-glycolic acid copolymer, polylactic acid-polyethyleneglycolcopolymer or polyglycolic acid-polyethyleneglycol copolymer), a polymerof an alkyl alpha-cyanoacrylate (for example poly(butyl2-cyanoacrylate)), a polyalkylene oxalate (for example polytrimethyleneoxalate or polytetramethylene oxalate), a polyortho ester, apolycarbonate (for example polyethylene carbonate orpolyethylenepropylene carbonate), a polyortho-carbonate, a polyaminoacid (for example poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamicacid or poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and thelike, and one or more of these polymers can be used.

If the polymers are copolymers, they may be any of random, block and/orgraft copolymers. When the above alpha-hydroxycarboxylic acids,hydroxydicarboxylic acids and hydroxytricarboxylic acids have opticalactivity in their molecules, any one of D-isomers, L-isomers and/orDL-isomers may be used. Among others, alpha-hydroxycarboxylic acidpolymer (preferably lactic acid-glycolic acid polymer), its ester,poly-alpha-cyanoacrylic acid esters, etc. may be used, and lacticacid-glycolic acid copolymer (also referred to aspoly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), andhereinafter referred to as PLGA) are preferred. Thus, in one aspect thepolymer useful for the polymeric matrix is PLGA. As used herein, theterm PLGA includes polymers of lactic acid (also referred to aspolylactide, poly(lactic acid), or PLA). Most preferably, the polymer isthe biodegradable poly(d,l-lactide-co-glycolide) polymer.

In a preferred embodiment, the polymeric matrix of the invention is abiocompatible and biodegradable polymeric material. The term“biocompatible” is defined as a polymeric material that is not toxic, isnot carcinogenic, and does not significantly induce inflammation in bodytissues. The matrix material should be biodegradable wherein thepolymeric material should degrade by bodily processes to productsreadily disposable by the body and should not accumulate in the body.The products of the biodegradation should also be biocompatible with thebody in that the polymeric matrix is biocompatible with the body.Particular useful examples of polymeric matrix materials includepoly(glycolic acid), poly-D,L-lactic acid, poly-L-lactic acid,copolymers of the foregoing, poly(aliphatic carboxylic acids),copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates),poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,poly(glycolic acid-caprolactone), polyanhydrides, and natural polymersincluding albumin, casein, and waxes, such as, glycerol mono- anddistearate, and the like. The preferred polymer for use in the practiceof this invention is dl(polylactide-co-glycolide). It is preferred thatthe molar ratio of lactide to glycolide in such a copolymer be in therange of from about 75:25 to 50:50.

Useful PLGA polymers may have a weight-average molecular weight of fromabout 5,000 to 500,000 Daltons, preferably about 150,000 Daltons.Dependent on the rate of degradation to be achieved, different molecularweight of polymers may be used. For a diffusional mechanism of drugrelease, the polymer should remain intact until all of the drug isreleased from the polymeric matrix and then degrade. The drug can alsobe released from the polymeric matrix as the polymeric excipientbioerodes.

The PLGA may be prepared by any conventional method, or may becommercially available. For example, PLGA can be produced byring-opening polymerization with a suitable catalyst from cycliclactide, glycolide, etc. (see EP-0058481B2; Effects of polymerizationvariables on PLGA properties: molecular weight, composition and chainstructure).

It is believed that PLGA is biodegradable by means of the degradation ofthe entire solid polymer composition, due to the break-down ofhydrolysable and enzymatically cleavable ester linkages under biologicalconditions (for example in the presence of water and biological enzymesfound in tissues of warm-blooded animals such as humans) to form lacticacid and glycolic acid. Both lactic acid and glycolic acid arewater-soluble, non-toxic products of normal metabolism, which mayfurther biodegrade to form carbon dioxide and water. In other words,PLGA is believed to degrade by means of hydrolysis of its ester groupsin the presence of water, for example in the body of a warm-bloodedanimal such as man, to produce lactic acid and glycolic acid and createthe acidic microclimate. Lactic and glycolic acid are by-products ofvarious metabolic pathways in the body of a warm-blooded animal such asman under normal physiological conditions and therefore are welltolerated and produce minimal systemic toxicity.

In another embodiment, the polymeric matrix useful for the invention maycomprise a star polymer wherein the structure of the polyester isstar-shaped. These polyesters have a single polyol residue as a centralmoiety surrounded by acid residue chains. The polyol moiety may be, e.g., glucose or, e. g., mannitol. These esters are known and described inGB 2,145,422 and in U.S. Pat. No. 5,538,739, the contents of which areincorporated by reference.

The star polymers may be prepared using polyhydroxy compounds, e. g.,polyol, e.g., glucose or mannitol as the initiator. The polyol containsat least 3 hydroxy groups and has a molecular weight of up to about20,000 Daltons, with at least 1, preferably at least 2, e.g., as a mean3 of the hydroxy groups of the polyol being in the form of ester groups,which contain polylactide or co-polylactide chains. The branchedpolyesters, e.g., poly (d, l-lactide-co-glycolide) have a centralglucose moiety having rays of linear polylactide chains.

The depot compositions of the invention (e.g., Compositions 6 and6.1-6.10, in a polymer matrix) as hereinbefore described may comprisethe polymer in the form of microparticles or nanoparticles, or in aliquid form, with the Compounds of the Invention dispersed orencapsulated therein. “Microparticles” is meant solid particles thatcontain the Compounds of the Invention either in solution or in solidform wherein such compound is dispersed or dissolved within the polymerthat serves as the matrix of the particle. By an appropriate selectionof polymeric materials, a microparticle formulation can be made in whichthe resulting microparticles exhibit both diffusional release andbiodegradation release properties.

When the polymer is in the form of microparticles, the microparticlesmay be prepared using any appropriate method, such as by a solventevaporation or solvent extraction method. For example, in the solventevaporation method, the Compounds of the Invention and the polymer maybe dissolved in a volatile organic solvent (for example a ketone such asacetone, a halogenated hydrocarbon such as chloroform or methylenechloride, a halogenated aromatic hydrocarbon, a cyclic ether such asdioxane, an ester such as ethyl acetate, a nitrile such as acetonitrile,or an alcohol such as ethanol) and dispersed in an aqueous phasecontaining a suitable emulsion stabilizer (for example polyvinylalcohol, PVA). The organic solvent is then evaporated to providemicroparticles with the Compounds of the Invention encapsulated therein.In the solvent extraction method, the Compounds of the Invention andpolymer may be dissolved in a polar solvent (such as acetonitrile,dichloromethane, methanol, ethyl acetate or methyl formate) and thendispersed in an aqueous phase (such as a water/PVA solution). Anemulsion is produced to provide microparticles with the Compounds of theInvention encapsulated therein. Spray drying is an alternativemanufacturing technique for preparing the microparticles.

Another method for preparing the microparticles of the invention is alsodescribed in both U.S. Pat. Nos. 4,389,330 and 4,530,840.

The microparticle of the present invention can be prepared by any methodcapable of producing microparticles in a size range acceptable for usein an injectable composition. One preferred method of preparation isthat described in U.S. Pat. No. 4,389,330. In this method the activeagent is dissolved or dispersed in an appropriate solvent. To theagent-containing medium is added the polymeric matrix material in anamount relative to the active ingredient that provides a product havingthe desired loading of active agent. Optionally, all of the ingredientsof the microparticle product can be blended in the solvent mediumtogether.

Solvents for the Compounds of the Invention and the polymeric matrixmaterial that can be employed in the practice of the present inventioninclude organic solvents, such as acetone; halogenated hydrocarbons,such as chloroform, methylene chloride, and the like; aromatichydrocarbon compounds; halogenated aromatic hydrocarbon compounds;cyclic ethers; alcohols, such as, benzyl alcohol; ethyl acetate; and thelike. In one embodiment, the solvent for use in the practice of thepresent invention may be a mixture of benzyl alcohol and ethyl acetate.Further information for the preparation of microparticles useful for theinvention can be found in U.S. Patent Publication Number 2008/0069885,the contents of which are incorporated herein by reference in theirentirety.

The amount of the Compounds of the present disclosure incorporated inthe microparticles usually ranges from about 1 wt % to about 90 wt. %,preferably 30 to 50 wt. %, more preferably 35 to 40 wt. %. By weight %is meant parts of the Compounds of the present disclosure per totalweight of microparticle.

The pharmaceutical depot compositions may comprise apharmaceutically-acceptable diluent or carrier, such as a water misciblediluent or carrier.

Details of Osmotic-controlled Release Oral delivery System compositionmay be found in EP 1 539 115 (U.S. Pub. No. 2009/0202631) and WO2000/35419, the contents of each of which are incorporated by referencein their entirety.

A “therapeutically effective amount” is any amount of the Compounds ofthe invention (for example as contained in the pharmaceutical depot)which, when administered to a subject suffering from a disease ordisorder, is effective to cause a reduction, remission, or regression ofthe disease or disorder over the period of time as intended for thetreatment.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Unless otherwise indicated, anamount of the Compound of the Invention for administration (whetheradministered as a free base or as a salt form) refers to or is based onthe amount of the Compound of the Invention in free base form (i.e., thecalculation of the amount is based on the free base amount).

Compounds of the Invention may be administered by any satisfactoryroute, including orally, parenterally (intravenously, intramuscular orsubcutaneous) or transdermally, but are preferably administered orally.In certain embodiment, the Compounds of the Invention, e.g., in depotformulation, is preferably administered parenterally, e.g., byinjection.

In general, satisfactory results for Method 1 and 1.1-1.46, Method 2 and2.1-2.20, and Method 3 and 3.1-3.40, or use of the Compounds of thepresent disclosure as hereinbefore described, e.g. for the treatment ofa combination of diseases such as a combination of at least depression,psychosis, e.g., (1) psychosis, e.g., schizophrenia, in a patientsuffering from depression; (2) depression in a patient suffering frompsychosis, e.g., schizophrenia; (3) mood disorders associated withpsychosis, e.g., schizophrenia, or Parkinson's disease; (4) sleepdisorders associated with psychosis, e.g., schizophrenia, or Parkinson'sdisease; and (5) substance addiction, substance use disorders and/orsubstance-induced disorders, as set forth above are indicated to beobtained on oral administration at dosages of the order from about 1 mgto 100 mg once daily, preferably 2.5 mg-50 mg, e.g., 2.5 mg, 5 mg, 10mg, 20 mg, 30 mg, 40 mg or 50 mg, once daily, preferably via oraladministration.

Satisfactory results for Method 2 or 2.1-2.20 or use of the Compounds ofthe present disclosure as hereinbefore described, e.g. for the treatmentof sleep disorder alone are indicated to be obtained on oraladministration at dosages of the order from about 2.5 mg-5 mg, e.g., 2.5mg, 3 mg, 4 mg or 5 mg, of a Compound of the Invention, in free orpharmaceutically acceptable salt form, once daily, preferably via oraladministration.

Satisfactory results for Method I-A or Method II-A, or any of 3.1-3.40are indicated to be obtained at less than 100 mg, preferably less than50 mg, e.g., less than 40 mg, less than 30 mg, less than 20 mg, lessthan 10 mg, less than 5 mg, less than 2.5 mg, once daily. Satisfactoryresults for Method II-A or any of 3.1-3.40 are indicated to be obtainedat less than 5 mg, preferably less than 2.5 mg.

For treatment of the disorders disclosed herein wherein the depotcomposition is used to achieve longer duration of action, the dosageswill be higher relative to the shorter action composition, e.g., higherthan 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg, 1,000 mg, or greaterthan 1000 mg. Duration of action of the Compounds of the presentdisclosure may be controlled by manipulation of the polymer composition,i.e., the polymer:drug ratio and microparticle size. Wherein thecomposition of the invention is a depot composition, administration byinjection is preferred.

The pharmaceutically acceptable salts of the Compounds of the presentdisclosure can be synthesized from the parent compound which contains abasic or acidic moiety by conventional chemical methods. Generally, suchsalts can be prepared by reacting the free base forms of these compoundswith a stoichiometric amount of the appropriate acid in water or in anorganic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Further details for the preparation of these salts, e.g.,toluenesulfonic salt in amorphous or crystal form, may be found inPCT/US08/03340 and/or U.S. Provisional Appl. No. 61/036,069.

Pharmaceutical compositions comprising Compounds of the presentdisclosure may be prepared using conventional diluents or excipients (anexample include, but is not limited to sesame oil) and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

Methods of Making the Compounds of the Invention:

The Compounds of the present disclosure wherein X is —NH— or —N(CH₃)—and Y is —C(═O) may be prepared by reacting (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalineor its 1-methyl analog with 4-chloro-4′-fluorobutyrophenone, inaccordance with Scheme 1 below:

Compounds of the present disclosure wherein X is —NH— or —N(CH₃)— and Yis —CH(OH)— may be prepared by reacting the4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-oneproduced in Scheme 1 (or its 1-methyl analog) with a reducing agent, inaccordance with Scheme 2, below:

The reducing agent may be a metal hydride, e.g., sodium borohydride,sodium cyanoborohydride, lithium aluminum hydride, aluminum hydride,diisobutylaluminum hydride, preferably sodium borohydride. Furtherreagents for reduction of ketones may be found in Jerry March, AdvancedOrganic Chemistry, Reactions Mechanisms and Structures, p. 910-911,(1992, John Wiley & Sons, Inc.), Fourth Edition, the contents of whichare incorporated by reference.

Isolation or purification of the diastereomers of the Compounds of theInvention may be achieved by conventional methods known in the art,e.g., column purification, preparative thin layer chromatography,preparative HPLC, crystallization, trituration, simulated moving bedsand the like.

The Compounds of Formula I wherein Y is —CH(O—R₁)— and R₁ is other thanH can be prepared by several commonly used esterification methods suchas alcoholysis of acyl halides, anhydrides or active esters. Forexample, The Compound of Formula I, wherein R₁ is —C(O)— alkyl may beprepared by reacting:

-   -   (a) L-C(O)—C₁₋₂₁ alkyl, wherein L is a leaving group such as a        halo group (for example, chloro or bromo),        trifluoromethylsulfonyloxy (—OSO₂CF₃), tosyloxy        (—O—S(O)₂—C₆H₄—CH₃), methylsulfonyloxy (—O—S(O)₂—CH₃),        1H-benzo[d][1,2,3]triazol-1-yloxy or succinimidyloxy group,    -   with    -   (b) the Compound of Formula I wherein Y is —C(H)(OH),        preferably in the presence of a base (e.g., diisopropylamine,        triethyl amine or pyridine). For example L-C(O)—C₁₋₂₁alkyl is an        acetyl halide, decanoyl halide or heptanoyl halide, which may be        prepared by reacting HO—C(O)—C₁₋₂₁ alkyl, e.g., with thionyl        chloride, P(X′)₃ or P(X′)₅ wherein X′ is Cl or Br. Wherein L is        tosyloxy-C(O)—C₁₋₂₁ alkyl or methylsulfonyloxy-C(O)—C₁₋₂₁alkyl,        these compounds may be prepared by reacting HO—C(O)—C₁₋₂₁alkyl        with tosyl-chloride or mesyl-chloride, preferably in the        presence of a base such as pyridine. Synthesis of the Compound        of Formula II-A where R₁ is other than H may be summarized in        Scheme 3 below:

Alternatively, the synthesis of the compound of Formula II-A where R₁ isother than H maybe achieved by reacting HO—C(O)—C₁₋₂₁alkyl with (i) acompound of Formula I wherein Y is —C(H)(OH) in the presence of a basesuch as DIEPA and NEt₃, and (ii) a dehydrating or coupling reagent suchas 2-fluoro-1-ethyl pyridinium tetrafluoroborate (FEP),tetramethylfluoromamidinium hexafluorophosphate (TFFH) or1,1,3,3-bis(tetramethylene) chlorouronium hexafluorophosphate (PyClU).

Salts of the Compounds of the present disclosure may be prepared assimilarly described in U.S. Pat. Nos. 6,548,493; 7,238,690; 6,552,017;6,713,471; 7,183,282; U.S. RE39680; U.S. RE39679; and WO 2009/114181,the contents of each of which are incorporated by reference in theirentirety.

Diastereomers of prepared compounds can be separated by, for example,HPLC using CHIRALPAK® AY-H, 5μ, 30×250 mm at room temperature and elutedwith 10% ethanol/90% hexane/0.1% dimethylethylamine. Peaks can bedetected at 230 nm to produce 98-99.9% ee of the diastereomer.

Example 1: Synthesis of4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one

(6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8-carboxylicacid ethyl ester (6.4 g, 21.2 mmol) is suspended in HBr acetic acidsolution (64 mL, 33% w/w) at room temperature. The mixture is heated at50° C. for 16 h. After cooling, and treatment with ethyl acetate (300mL), the mixture is filtered. The filter cake is washed with ethylacetate (300 mL), and then dried under vacuum. The obtained HBr salt isthen suspended in methanol (200 mL), and cooled with dry ice inisopropanol. Under vigorous stirring, ammonia solution (10 mL, 7N inmethanol) is added slowly to the suspension to adjust the pH of themixture to 10. The obtained mixture is dried under vacuum withoutfurther purification to give crude (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(8.0 g), which is used directly in the next step. MS (ESI) m/z 230.2[M+H]⁺.

The crude (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline(1.4 g) is dissolved in DMF (14 mL), and then KI (2.15 g) and4-Chloro-4′-fluorobutyrophenone (2 mL) are added successively. Themixture is degassed with argon, followed by addingN,N-diisopropylethylamine(DIPEA, 2 mL). The mixture is heated at 78° C.for 2 h. After cooling, the solvents are removed under reduced pressure.The dark brown residue is suspended in dichloromethane (100 mL) and thenextracted with water (30 mL). The organic layer is separated, and driedover K₂CO₃. After filtration, the solvents are removed under reducedpressure. The obtained crude product is purified by silica gel columnchromatography eluting with 0-10% of methanol in ethyl acetatecontaining 0.1% of 7N ammonia in methanol to yield4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-oneas a light yellow solid (767 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s,1H), 8.1-8.0 (m, 2H), 7.3 (dd, J=8.86 Hz, 2H), 6.8 (d, J=7.25 Hz, 1H),6.6 (dd, J=7.55 Hz, 1H), 6.6 (d, J=7.74 Hz, 1H), 3.8 (d, J=14.49 Hz,1H), 3.3-3.3 (m, 1H), 3.2-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0 (t, J=6.88Hz, 2H), 2.8-2.8 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.2 (m, 2H), 2.1-2.0 (m,1H), 1.9-1.8 (m, 1H), 1.8 (t, J=6.99 Hz, 2H), 1.6 (t, J=11.25 Hz, 2H).MS (ESI) m/z 394.2 [M+H]+.

Example 2: Synthesis of4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol

4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one(50 mg, 0.127 mmol) is dissolved in methanol (5 mL). Under stirring,NaBH₄ (31 mg, 0.82 mmol) is added in batches. After the completion ofthe addition, the mixture is stirred at room temperature for 30 min.Methanol is evaporated under reduced pressure. The residue is dissolvedin dichloromethane (10 mL) and then extracted with water (2×0.5 mL). Thecombined organic phase is dried over K₂CO₃. After filtration, thefiltrate is concentrated under reduced pressure and then further driedunder vacuum to give4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-olas a pale yellow foamy solid (45 mg, yield 90%). ¹H NMR (500 MHz,DMSO-d₆) δ 10.3 (s, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m, 2H), 6.7 (d,J=7.29 Hz, 1H), 6.7-6.6 (m, 1H), 6.6 (d, J=7.74 Hz, 1H), 5.4 (s, 1H),4.7-4.4 (m, 1H), 3.8 (d, J=14.49 Hz, 1H), 3.3-3.3 (m, 1H), 3.3-3.2 (m,1H), 3.2-3.1 (m, 1H), 2.8-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.3-2.1 (m, 2H),2.1-2.0 (m, 1H), 2.0-1.9 (m, 1H), 1.8-1.7 (m, 1H), 1.7-1.5 (m, 3H),1.5-1.4 (m, 1H), 1.4-1.3 (m, 1H). MS (ESI) m/z 396.2 [M+H]+.

Example 3: Synthesis of(6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

A mixture of(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one(100 mg, 0.436 mmol), 1-(3-chloroproxy)-4-fluorobenzene (100 μL, 0.65mmol) and KI (144 mg, 0.87 mmol) in DMF (2 mL) is degassed with argonfor 3 minutes and DIPEA (150 μL, 0.87 mmol) is added. The resultingmixture is heated to 78° C. and stirred at this temperature for 2 h. Themixture is cooled to room temperature and then filtered. The filter cakeis purified by silica gel column chromatography using a gradient of0-100% ethyl acetate in a mixture of methanol/7N NH₃ in methanol (1:0.1v/v) as an eluent to produce partially purified product, which isfurther purified with a semi-preparative HPLC system using a gradient of0-60% acetonitrile in water containing 0.1% formic acid over 16 min toobtain the title product as a solid (50 mg, yield 30%). MS (ESI) m/z406.2 [M+1]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 10.3 (s, 1H), 7.2-7.1 (m, 2H),7.0-6.9 (m, 2H), 6.8 (dd, J=1.03, 7.25 Hz, 1H), 6.6 (t, J=7.55 Hz, 1H),6.6 (dd, J=1.07, 7.79 Hz, 1H), 4.0 (t, J=6.35 Hz, 2H), 3.8 (d, J=14.74Hz, 1H), 3.3-3.2 (m, 3H), 2.9 (dd, J=6.35, 11.13 Hz, 1H), 2.7-2.6 (m,1H), 2.5-2.3 (m, 2H), 2.1 (t, J=11.66 Hz, 1H), 2.0 (d, J=14.50 Hz, 1H),1.9-1.8 (m, 3H), 1.7 (t, J=11.04 Hz, 1H).

Example 4: Cellular and Nuclear Receptor Functional Assays

Cellular and Nuclear Receptor Functional Assays are performed on thecompounds of Formula II-B and II-C according to the procedure of Wang,J. B. et al. (1994), FEBS Lett., 338:217-222. The compounds are testedat several concentrations to determine their IC₅₀ or EC₅₀. Cellularagonist effects are calculated as percent of control response to a knownreference agonist for each target and cellular antagonist effect iscalculated as a percent inhibition of control reference agonist responsefor each target.

The following assay is performed to determine the effect of the Compoundof Formula II-B on the μ (MOP) (h) receptor:

Measured Detection Assay (Receptor) Source Stimulus Incubation ComponentMethod μ (MOP) (h) human none 10 min @ cAMP HTRF (agonist effect)recombinant (0.3 μM 37° C. (CHO cells) DAMGO for control) μ (MOP) (h)human DAMGO 10 min @ cAMP HTRF (antagonist effect) recombinant (20 nM)37° C. (CHO cells)

For the antagonists, the apparent dissociation constants (K_(B)) arecalculated using the modified Cheng Prusoff equation:

$K_{B} = \frac{{IC}_{50}}{1 + \left( {A/{EC}_{50A}} \right)}$where A=concentration of reference agonist in the assay, andEC_(50A)=EC₅₀ value of the reference agonist.

The compound of Formula II-B is found to have a μ (MOP) (h) (antagonisteffect) with an IC₅₀ of 1.3×10⁻⁶M; and a K_(B) of 1.4×10⁻⁷M; and thecompound of Formula II-C is found to have an IC₅₀ greater than 1×10⁻⁵,which was the highest concentration tested.

The results are expressed as a percent of control agonist response:

$\frac{{measured}\mspace{14mu}{response}}{{control}\mspace{14mu}{response}} \times 100$and as a percent inhibition of control agonist response:

$100 - \left( {\frac{{measured}\mspace{14mu}{response}}{{control}\mspace{14mu}{response}} \times 100} \right)$obtained in the presence of the Compound of Formula II-B or II-C.

The EC₅₀ values (concentration producing a half-maximal response) andIC₅₀ values (concentration causing a half-maximal inhibition of thecontrol agonist response) are determined by non-linear regressionanalysis of the concentration-response curves generated with meanreplicate values using Hill equation curve fitting:

$Y = {D + \left\lbrack \frac{A - D}{1 + \left( {C/C_{50}} \right)^{nH}} \right\rbrack}$where Y=response, A=left asymptote of the curve, D=right asymptote ofthe curve, C=compound concentration, and C₅₀=EC₅₀ or IC₅₀, and nH=slopefactor. The analysis is performed using software developed in-house andvalidated by comparison with data generated by the commercial softwareSigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.).

Example 5: Receptor Binding Profile of Compound of Formulas II-B andII-C

Receptor binding is determined for the Compounds of Formulas II-A andII-B using the tosylate salt of the compound of Formula A as a control.The following literature procedures are used, each of which reference isincorporated herein by reference in their entireties: 5-HT_(2A): Bryant,H. U. et al. (1996), Life Sci., 15:1259-1268; D2: Hall, D. A. andStrange, P. G. (1997), Brit. J. Pharmacol., 121:731-736; D1: Zhou, Q. Y.et al. (1990), Nature, 347:76-80; SERT: Park, Y. M. et al. (1999), Anal.Biochem., 269:94-104; Mu opiate receptor: Wang, J. B. et al. (1994),FEBS Lett., 338:217-222.

In general, the results are expressed as a percent of control specificbinding:

$\frac{{measured}\mspace{14mu}{specific}\mspace{14mu}{binding}}{{control}\mspace{14mu}{specific}\mspace{14mu}{binding}} \times 100$and as a percent inhibition of control specific binding:

$100 - \left( {\frac{{measured}\mspace{14mu}{specific}\mspace{14mu}{binding}}{{control}\mspace{14mu}{specific}\mspace{14mu}{binding}} \times 100} \right)$obtained in the presence of the test compounds.

The IC₅₀ values (concentration causing a half-maximal inhibition ofcontrol specific binding) and Hill coefficients (nH) are determined bynon-linear regression analysis of the competition curves generated withmean replicate values using Hill equation curve fitting:

$Y = {D + \left\lbrack \frac{A - D}{1 + \left( {C/C_{50}} \right)^{nH}} \right\rbrack}$where Y=specific binding, A=left asymptote of the curve, D=rightasymptote of the curve, C=compound concentration, C₅₀=IC₅₀, and nH=slopefactor. This analysis was performed using in-house software andvalidated by comparison with data generated by the commercial softwareSigmaPlot® 4.0 for Windows® (© 1997 by SPSS Inc.). The inhibitionconstants (Ki) were calculated using the Cheng Prusoff equation:

${Ki} = \frac{{IC}_{50}}{\left( {1 + {L/K_{D}}} \right)}$where L=concentration of radioligand in the assay, and K_(D)=affinity ofthe radioligand for the receptor. A Scatchard plot is used to determinethe K_(D).

The following receptor affinity results are obtained, using the tosylatesalt of a Compound of Formula A as a control:

Formula A Formula II-B Formula II-C (tosylate (Ex. 1) (Ex. 2) Example 3salt) Receptor Ki (nM) or maximum inhibition 5-HT_(2A) 11 31% inhibitionat 8.3 10 240 nM D2 47% inhibition 11% inhibition at 160 49 at 240 nM240 nM D1 22 13% inhibition at 50 41 100 nM SERT 44% inhibition Noinhibition 590 16 at 240 nM seen Mu opiate 22 85 11 >10,000 receptor

Example 6: DOI-induced Head Twitch Model in Mice

R-(−)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of theserotonin 5-HT₂ receptor family. When administered to mice, it producesa behavioral profile associated with frequent head twitches. Thefrequency of these head twitches during a predetermined period of timecan be taken as an estimate of 5-HT₂ receptor agonism in the brain.Conversely, this behavioral assay can be used to determine 5-HT₂receptor antagonism in the brain by administering the DOI with orwithout an antagonist and recording the reduction in DOI-induced headtwitches after the administration of the antagonist.

The method of Darmani et al., Pharmacol Biochem Behav. (1990) 36:901-906(the contents of which are incorporated by reference in their entirety)is used with some modifications. (±)-DOI HCl is injected subcutaneouslyand the mice are immediately placed in a conventional plastic cage. Thenumber of head twitches is counted during 6 min, beginning 1 min afterDOI administration. The tested compound is administered orally 0.5 hrbefore the injection of DOI. Results area calculated as the EC50 forreducing DOI-induced head twitches. The results are shown in thefollowing Table:

Compound EC₅₀ (mg/kg, p.o.) Example 1 (Formula II-B) 0.23 Example 2(Formula II-C) 2.03 Example 3 0.44 Formula A 0.09 Formula B 0.31The results show that the compounds of Example 1 and 3 potently blockDOI head twitch, comparable to the reference compounds Formula A and C,and consistent with the in-vitro 5-HT2A results shown in Example 5. Incontrast, the compound of Example 2 is relatively inactive in thisfunctional assay, confirming that this compound is relatively weaker inits serotonin receptor antagonism than other structurally similarcompounds.

Example 7: Mouse Tail Flick Assay

The Mouse Tail Flick Assay is a measure of an analgesia, indicated bythe pain reflex threshold of restrained mice. Male CD-1 mice arepositioned with their tails under a focused beam of high-intensityinfrared heat source, resulting in heating of the tail. The amount oftime (latency) between turning on heating instrument and the flicking ofthe mouse's tail out of path of the heat source is recorded.Administration of morphine results in analgesia, and this produces adelay in the mouse's reaction to the heat (increased latency). Prioradministration of a morphine antagonist, i.e., naloxone, reverses theeffect and results in normal latency time. This test is used as afunctional assay to gauge antagonism of mu-opiate receptors.

Ten male CD-1 mice (about 8 weeks of age) are assigned to each of fivetreatment groups. The groups are treated as follows: Group (1) [negativecontrol]: administered 0.25% methylcellulose vehicle p.o., 60 minutesbefore the tail flick test, and saline vehicle 30 minutes before thetail flick test; Group (2) [positive control]: administered 0.25%methylcellulose vehicle p.o., 60 minutes before the test, and 5 mg/kgmorphine in saline 30 minutes before the test; Group (3) [positivecontrol]: administered 3 mg/kg naloxone in saline 50 minutes before thetest, and 5 mg/kg morphine in saline 30 minutes before the test; Groups(4)-(6): administered either 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of the testcompound in 0.25% methylcellulose vehicle p.o., 60 minutes before thetest, and 5 mg/kg morphine in 30 minutes before the test. The experimentis repeated for the compounds of Example 1 and Example 3. The resultsare shown in the following table as mean latency measured in seconds:

Group 4 Group 5 Group 6 Group 1 Group 2 Group 3 Cmpd/Mor Cmpd/MorCmpd/Mor Veh/Veh Veh/Mor Nal/Mor (0.1 mg/kg) (0.3 mg/kg) (1 mg/kg) Ex. 11.028 9.361 2.496 8.870 6.907 6.240 Ex. 3 0.887 8.261 3.013 6.947 5.8536.537

The results demonstrate that the compounds of Example 1 and Example 3both exert a dose-dependent blockade of morphine-induced mu-opiatereceptor activity.

Example 8: CNS Phosphoprotein Profile

A comprehensive molecular phosphorylation study is also carried out toexamine the central nervous system (CNS) profile of the compounds ofExample 1 and Example 3. The extent of protein phosphorylation forselected key central nervous system proteins is measured in mice nucleusaccumbens. Examined proteins include ERK1, ERK2, Glu1, NR2B and TH(tyrosine hydroxylase), and the compounds of Example 1 and 3 werecompared to the antipsychotic agents risperidone and haloperidol.

Mice were treated with the compound of Example 1 or 3 at 3 mg/kg, orwith haloperidol at 2 mg/kg. Mice were killed 30 minutes to 2 hourspost-injection by focused microwave cranial irradiation, which preservesbrain phosphoprotein as it exists at the time of death. Nucleusaccumbens was then dissected from each mouse brain, sliced and frozen inliquid nitrogen. Samples were further prepared for phosphoproteinanalysis via SDS-PAGE electrophoresis followed byphosphoprotein-specific immunoblotting, as described in Zhu H, et al.,Brain Res. 2010 Jun. 25; 1342:11-23. Phosphorylation at each site wasquantified, normalized to total levels of the protein(non-phosphorylated), and expressed as percent of the level ofphosphorylation in vehicle-treated control mice.

The results demonstrate that neither the compound of Example 1 nor ofExample 3 has a significant effect on tyrosine hydroxylasephosphorylation at Ser40 at 30 minutes or 60 minutes, in contrast tohaloperidol which produces a greater than 400% increase, and risperidonewhich produces a greater than 500% increase, in TH phosphorylation. Thisdemonstrates that inventive compounds do not disrupt dopaminemetabolism.

The results further demonstrate that neither the compound of Example 1nor of Example 3 has a significant effect on NR2B phosphorylation atTyr1472 at 30-60 minutes. The compounds produce a slight increase inGluR1 phosphorylation at Ser845, and a slight decrease in ERK2phosphorylation at Thr183 and Tyr185.

Example 9: Mouse Marble-Burying Study (OCD Model)

The marble burying test is used to measure repetitive andanxiety-related behavior in rodents. It is based on the observation thatrats and mice will bury either harmful or harmless objects in theirbedding, and it has been used as an animal model to measure the effectof pharmacological interventions in treatment of repetitive behaviordisorders, such as OCD.

Mice are first divided up into four treatment groups: (1) vehiclenegative control, (2) 0.3 mg/kg compound of Example 3, (3) 1.5 mg/kgcompound of Example 3, and (4) 20 mg/kg MPEP(2-methyl-6-(phenylethynyl)pyridine) positive control. MPEP is aselective mGluR5 glutamate receptor antagonist. Mice in groups (2) and(3) are orally administered the compound of Example 3 at the stateddosage in a 0.5% methylcellulose aqueous vehicle 30 minutes prior to thetest. Mice in groups (1) are orally administered the vehicle, and micein group (4) are given an intraperitoneal injection of MPEP just priorto the start of the test.

The test is conducted in rectangular cages with 4-5 cm of wood chipbedding in a room with the window shades lowered and the door closed tominimize distractions. Fifteen clean marbles are evenly spaced on top ofthe bedding in three rows of five marbles. One mouse is placed in eachcage. The mouse and cage is left undisturbed for 30 minutes. At the endof the test, the mouse is removed and the number of marbles buried to atleast ⅔ of their depth is counted. The results are shown in thefollowing table:

Group Marbles Buried (1) Vehicle 13.2 (2) 0.3 mg/kg Ex. 3 9.3 (3) 1.5mg/kg Ex. 3 4.7 (4) MPEP 0.2

The results demonstrate that compared to the control, there is astatistically significant decrease in marble burying for the micetreated with 0.3 mg/kg of the compound of Example 3 (p<0.01) and with1.5 mg/kg of the compound of Example 3 (p<0.001). In addition, there isa clear dose-response relationship evident.

Example 10: Mu-Opiate Receptor Activity Assays

The compounds of Example 1 and 3 are tested in CHO-K1 cells expressinghOP3 (human mu-opiate receptor μl subtype) using an HTRF-based cAMPassay kit (cAMP Dynamic2 Assay Kit, from Cisbio, #62AM4PEB). Frozencells are thawed in a 37° C. water bath and are resuspended in 10 mL ofHam's F-12 medium containing 10% FBS. Cells are recovered bycentrifugation and resuspended in assay buffer (5 nM KCl, 1.25 mM MgSO₄,124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KH₂PO₄, 1.45 mMCaCl₂), 0.5 g/L protease-free BSA, supplemented with 1 mM IBMX).Buprenorphine, a mu-opiate receptor partial agonist, and naloxone, amu-opiate receptor antagonist, and DAMGO, a synthetic opioid peptidefull agonist, are run as controls.

For agonist assays, 12 μL of cell suspension (2500 cells/well) are mixedwith 6 μL forksolin (10 μM final assay concentration), and 6 μL of thetest compound at increasing concentrations are combined in the wells ofa 384-well white plate and the plate is incubated for 30 minutes at roomtemperature. After addition of lysis buffer and one hour of furtherincubation, cAMP concentrations are measured according to the kitinstructions. All assay points are determined in triplicate. Curvefitting is performed using XLfit software (IDBS) and EC₅₀ values aredetermined using a 4-parameter logistic fit. The agonist assay measuresthe ability of the test compound to inhibit forskolin-stimulated cAMPaccumulation.

For antagonist assays, 12 μL of cell suspension (2500 cells/well) aremixed with 6 μL of the test compound at increasing concentrations, andcombined in the wells of a 384-well white plate and the plate isincubated for 10 minutes at room temperature. 6 μL of a mixture of DAMGO(D-Ala²-N-MePhe⁴-Gly-ol-enkephelin, 10 nM final assay concentration) andforksolin (10 μM final assay concentration) are added, and the platesare incubated for 30 minutes at room temperature. After addition oflysis buffer, and one hour of further incubation, cAMP concentrationsare measured according the kit instructions. All assay points aredetermined in triplicate. Curve fitting is performed using XLfitsoftware (IDBS) and IC₅₀ values are determined using a 4-parameterlogistic fit. Apparent dissociation constants (K_(B)) are calculatedusing the modified Cheng-Prusoff equation. The antagonist assay measuresthe ability of the test compound to reverse the inhibition offorskolin-induced cAMP accumulation caused by DAMGO.

The results are shown in FIGS. 1 and 2, and in the Table below. Theresults demonstrate that the compound of Example 3 is a weak antagonistof the Mu receptor, showing much higher IC₅₀ compared to naloxone, andthat it is a moderately strong partial agonist, showing about 22%activity relative to DAMGO (as compared to about 79% activity forbuprenorphine relative to DAMGO). The compound of Example 1 is alsoshown to have moderately strong partial agonist activity.

Compound Antagonist IC50 (nM) Agonist EC50 (nM) KB (nM) Naloxone 5.80 —0.65 DAMGO — 1.56 — Buprenorphine — 0.95 — Cmpd. Ex. 3 641 64.5 71.4Cmpd Ex. 1 — 140 —

Buprenorphine is a drug used for chronic pain treatment and for opiatewithdrawal, but it suffers from the problem that users can becomeaddicted due to its high partial agonist activity. To offset this, thecommercial combination of buprenorphine with naloxone is used (sold asSuboxone). Without being bound by theory, it is believed that thecompounds of the present invention, which are weaker partial Mu agoniststhan buprenorphine, with some moderate antagonistic activity, will allowa patient to be more effectively treated for pain and/or opiatewithdrawal with lower risks of addiction.

What is claimed:
 1. A compound according to Formula I:

wherein: X is NH; L is O; Z is —O— or —C(O)—; in free form, salt form,or pharmaceutically acceptable salt form.
 2. The compound according toclaim 1, wherein Z is —C(═O)—.
 3. The compound according to claim 1,wherein Z is O—.
 4. The compound according to claim 3 in free form. 5.The compound according to claim 4 in solid form.
 6. The compoundaccording to claim 3 in pharmaceutically acceptable salt form.
 7. Thecompound according to claim 6, wherein the compound is in acid additionsalt form with an acid selected from glutamic acid, tartaric acid, malicacid or ascorbic acid.
 8. A pharmaceutical composition comprising thecompound according to claim 1 in admixture with a pharmaceuticallyacceptable diluent or carrier.
 9. The composition according to claim 8,wherein the pharmaceutically acceptable diluent or carrier comprises apolymeric matrix.
 10. The composition according to claim 9, wherein thepolymeric matrix comprises a biodegradablepoly(d,l-lactide-co-glycolide) microsphere.
 11. A pharmaceuticalcomposition comprising the compound according to claim 3 in admixturewith a pharmaceutically acceptable diluent or carrier.
 12. Apharmaceutical composition comprising the compound according to claim 4in admixture with a pharmaceutically acceptable diluent or carrier. 13.The composition according to claim 12, wherein the pharmaceuticallyacceptable diluent or carrier comprises a polymeric matrix.
 14. Thecomposition according to claim 13, wherein the polymeric matrixcomprises a biodegradable poly(d,l-lactide-co-glycolide) microsphere.15. A pharmaceutical composition comprising the compound according toclaim 7 in admixture with a pharmaceutically acceptable diluent orcarrier.
 16. The composition according to claim 15, wherein thepharmaceutically acceptable diluent or carrier comprises a polymericmatrix.
 17. The composition according to claim 16, wherein the polymericmatrix comprises a biodegradable poly(d,l-lactide-co-glycolide)microsphere.